Tamper-resistant dosage form containing ethylene-vinyl acetate polymer

ABSTRACT

The invention relates to a tamper-resistant, oral pharmaceutical dosage form comprising a pharmacologically active ingredient having psychotropic action and an ethylene-vinyl acetate (EVA) polymer which provides resistance against solvent extraction, resistance against grinding, and resistance against dose-dumping in aqueous ethanol.

This application claims priority of European Patent Application No. EP13176303.9, filed Jul. 12, 2013, the contents of which are incorporatedherein by reference.

FIELD OF THE INVENTION

The invention relates to a tamper-resistant, oral pharmaceutical dosageform comprising a pharmacologically active ingredient havingpsychotropic action and an ethylene-vinyl acetate (EVA) polymer, whichdosage form provides resistance against solvent extraction, resistanceagainst grinding, and resistance against dose-dumping in aqueousethanol.

BACKGROUND OF THE INVENTION

A large number of pharmacologically active substances have a potentialfor being abused or misused, i.e. they can be used to produce effectswhich are not consistent with their intended use. Thus, e.g. opioidswhich exhibit an excellent efficacy in controlling severe to extremelysevere pain are frequently abused to induce euphoric states similar tobeing intoxicated. In particular, active substances which have apsychotropic effect are abused accordingly.

To enable abuse, the corresponding pharmaceutical dosage forms, such aspharmaceutical dosage forms or capsules are crushed, for example groundby the abuser, the active substance is extracted from the thus obtainedpowder using a preferably aqueous liquid and after being optionallyfiltered through cotton wool or cellulose wadding, the resultantsolution is administered parenterally, in particular intravenously. Thistype of dosage results in an even faster diffusion of the activesubstance compared to the oral abuse, with the result desired by theabuser, namely the kick. This kick or these intoxication-like, euphoricstates are also reached if the powdered pharmaceutical dosage form isadministered nasally, i.e. is sniffed.

Various concepts for the avoidance of drug abuse have been developed.

It has been proposed to incorporate in pharmaceutical dosage formsaversive agents and/or antagonists in a manner so that they only producetheir aversive and/or antagonizing effects when the pharmaceuticaldosage forms are tampered with. However, the presence of such aversiveagents is principally not desirable and there is a need to providesufficient tamper-resistance without relying on aversive agents and/orantagonists.

Another concept to prevent abuse relies on the mechanical properties ofthe pharmaceutical dosage forms, particularly an increased breakingstrength (resistance to crushing). The major advantage of suchpharmaceutical dosage forms is that comminuting, particularlypulverization, by conventional means, such as grinding in a mortar orfracturing by means of a hammer, is impossible or at least substantiallyimpeded. Thus, the pulverization, necessary for abuse, of thepharmaceutical dosage forms by the means usually available to apotential abuser is prevented or at least complicated. Suchpharmaceutical dosage forms are useful for avoiding drug abuse of thepharmacologically active ingredient contained therein, as they may notbe powdered by conventional means and thus, cannot be administered inpowdered form, e.g. nasally. The mechanical properties, particularly thehigh breaking strength of these pharmaceutical dosage forms renders themtamper-resistant. In the context of such tamper-resistant pharmaceuticaldosage forms it can be referred to, e.g., WO 2005/016313, WO2005/016314, WO 2005/063214, WO 2005/102286, WO 2006/002883, WO2006/002884, WO 2006/002886, WO 2006/082097, WO 2006/082099, andWO2009/092601.

Besides tampering of pharmaceutical dosage forms in order to abuse thedrugs contained therein, the potential impact of concomitant intake ofethanol on the in vivo release of drugs from modified release oralformulations (dose-dumping) has recently become an increasing concern.Controlled or modified release formulations typically contain a higheramount of the pharmacologically active ingredient relative to itsimmediate release counterpart. If the controlled release portion of theformulation is easily defeated, the end result is a potential increasein exposure to the active drug and possible safety concerns. In order toimprove safety and circumvent intentional tampering (e.g. dissolving acontrolled release pharmaceutical dosage form in ethanol to extract thedrug), a reduction in the dissolution of the modified release fractionsof such formulations, in ethanol, may be of benefit. Accordingly, theneed exists to develop new formulations having reduced potential fordose dumping in alcohol.

The properties of these pharmaceutical dosage forms of the prior art,however, are not satisfactory in every respect.

C. Vervaet et al., Eur. J. Pharm. Biopharm. 77, 2011, 297-305 discloseethylene vinyl acetate as matrix for oral sustained release dosage formswhich contain metoprolol tartrate as the pharmacologically activeingredient and are produced via hot-melt extrusion. C. Vervaet et al.,Eur. J. Pharm. Biopharm. 82, 2012, 526-533 discloses sustained releaseof metoprolol tartrate from hot-melt extruded matrices based on ethylenevinyl acetate and polyethylene oxide. B. Sreenivasa Rao et al., IndianJ. Pharm. Sci. 65, 2003, 496-502 disclose a method of preparation ofsintered matrix tablets of rifampicin with ethylene-vinyl acetatecopolymer for controlling the release rate. However, these referencesare fully silent on the possibility of preparing tamper-resistantpharmaceutical dosage forms from ethylene-vinyl acetate (EVA) polymers.

WO 2009/051819 A1 disclose implants for delivery of therapeutic agentssuch as opioids, and the manufacture and uses of such implants. WO03/070191 A1 discloses a transdermal-delivery device which is said to betamper-resistant and comprises an opioid, or a pharmaceuticallyacceptable salt thereof, and an acyl opiod antagonist, or apharmaceutically acceptable salt thereof.

It is an object of the invention to provide tamper-resistant anddose-dumping resistant, oral pharmaceutical dosage forms containing apharmacologically active ingredient having psychotropic action whichhave advantages compared to the pharmaceutical dosage forms of the priorart.

This object has been achieved as described hereinbelow.

It has been surprisingly found that a pharmaceutical dosage formcomprising ethylene-vinyl acetate (EVA) polymer and a pharmacologicallyactive ingredient having psychotropic action can be prepared, whereinthe pharmaceutical dosage form exhibits tamper resistance, especially interms of resistance against solvent extraction of the pharmacologicallyactive ingredient, resistance against grinding of the pharmaceuticaldosage form, respectively, and resistance against dose-dumping of thepharmacologically active ingredient in aqueous ethanol.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described in greater detail with reference tothe drawings, wherein:

FIG. 1 is a graph depicting the results of the sieving analysis referredto in Example 1;

FIG. 2 is a graph depicting the results of the sieving analysis referredto in Example 2;

FIG. 3 is a chart showing the release profiles of the indicatedexemplified embodiments;

FIG. 4 is a chart showing the release profiles of the indicatedexemplified embodiments;

FIG. 5 is a chart showing the release profiles of the indicatedexemplified embodiments;

FIG. 6 is a chart showing the release profiles of the indicatedexemplified embodiments;

FIG. 7 is a chart showing the release profiles of the indicatedexemplified embodiments; and

FIG. 8 is a chart showing the release profiles of the indicatedexemplified embodiments.

A first aspect of the invention relates to a tamper-resistant, oralpharmaceutical dosage form comprising a pharmacologically activeingredient having psychotropic action and an ethylene-vinyl acetate(EVA) polymer, which dosage form provides resistance against solventextraction, resistance against grinding, and resistance againstdose-dumping in aqueous ethanol.

Preferably, the pharmaceutical dosage form according to the invention isthermoformed, more preferably hot-melt extruded. Thermoformingpreferably means that in the course of the manufacture of thepharmaceutical dosage form the mixture comprising the EVA polymer andthe pharmacologically active ingredient is heated to a temperature aboveambient temperature, preferably at least 60° C. or at least 80° C., andcompressed, preferably at pressures of at least 1 bar or at least 2 bar,more preferably at least 10 bar or at least 30 bar. The compressionforce may be exerted prior to, during or subsequent to the applicationof heat.

As used herein, the term “pharmaceutical dosage form” refers to apharmaceutical entity that is comprised of a pharmacologically activeingredient and which is actually administered to, or taken by, apatient. It may be compressed or molded in its manufacture, and it maybe of almost any size, shape, weight, and color.

The pharmaceutical dosage form is preferably solid or semisolid.

Examples of pharmaceutical dosage forms according to the inventioninclude, but are not limited to, tablets, capsules, pills, granules,pellets, sachets and effervescent, powders, and the like. In anembodiment of the present invention, the composition is formulated in acapsule. In accordance with this embodiment, the pharmaceutical dosageform comprises a hard or soft gelatin capsule.

Most pharmaceutical dosage forms are intended to be swallowed whole andaccordingly, the pharmaceutical dosage forms according to the inventionare designed for oral administration.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is monolithic. In this regard, monolithic preferably meansthat the pharmaceutical dosage form is formed or composed of materialwithout joints or seams or consists of or constitutes a single unit.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention is not monolithic. Preferably, thepharmaceutical dosage form according to the invention ismultiparticulate, i.e. comprises a multitude of particles. An advantageof multiparticulate pharmaceutical dosage forms is that the particlesmay be mixed in different amounts to thereby produce pharmaceuticaldosage forms of different strengths.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention can be regarded as a MUPS formulation (multiple unitpellet system). Preferably, the pharmaceutical dosage form according tothe invention contains all ingredients in a dense compact unit which incomparison to capsules has a comparatively high density. Under thesecircumstances, the pharmaceutical dosage forms according to theinvention preferably comprise subunits having different morphology andproperties, namely drug-containing particles and an outer matrixmaterial, wherein the particles form a discontinuous phase within theouter matrix material. The constituents of the outer matrix material arepreferably different from the constituents of the drug-containingparticles. Preferably, the outer matrix material neither contains apharmacologically active ingredient having psychotropic action nor anEVA polymer.

The particles typically have mechanical properties that differ from themechanical properties of the outer matrix material. Preferably, theparticles have a higher mechanical strength than the outer matrixmaterial. The particles can preferably be visualized by conventionalmeans such as solid state nuclear magnetic resonance spectroscopy,raster electron microscopy, terahertz spectroscopy and the like.

The pharmaceutical dosage form according to the invention has preferablya total weight in the range of 0.01 to 1.5 g, more preferably in therange of 0.05 to 1.2 g, still more preferably in the range of 0.1 g to1.0 g, yet more preferably in the range of 0.2 g to 0.9 g, and mostpreferably in the range of 0.3 g to 0.8 g. In a preferred embodiment,the total weight of the pharmaceutical dosage form is within the rangeof 350±300 mg, more preferably 350±250 mg, still more preferably 350±200mg, yet more preferably 350±150 mg, most preferably 350±100 mg, and inparticular 350±50 mg. In another preferred embodiment, the total weightof the pharmaceutical dosage form is within the range of 500±450 mg,more preferably 500±300 mg, still more preferably 500±200 mg, yet morepreferably 500±150 mg, most preferably 500±100 mg, and in particular500±50 mg.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is a round pharmaceutical dosage form. Pharmaceuticaldosage forms of this embodiment preferably have a diameter in the rangeof about 1 mm to about 30 mm, in particular in the range of about 2 mmto about 25 mm, more in particular about 5 mm to about 23 mm, even morein particular about 7 mm to about 13 mm; and a thickness in the range ofabout 1.0 mm to about 12 mm, in particular in the range of about 2.0 mmto about 10 mm, even more in particular from 3.0 mm to about 9.0 mm,even further in particular from about 4.0 mm to about 8.0 mm.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention is an oblong pharmaceutical dosage form.Pharmaceutical dosage forms of this embodiment preferably have alengthwise extension (longitudinal extension) of about 1 mm to about 30mm, in particular in the range of about 2 mm to about 25 mm, more inparticular about 5 mm to about 23 mm, even more in particular about 7 mmto about 20 mm; a width in the range of about 1 mm to about 30 mm, inparticular in the range of about 2 mm to about 25 mm, more in particularabout 5 mm to about 23 mm, even more in particular about 7 mm to about13 mm; and a thickness in the range of about 1.0 mm to about 12 mm, inparticular in the range of about 2.0 mm to about 10 mm, even more inparticular from 3.0 mm to about 9.0 mm, even further in particular fromabout 4.0 mm to about 8.0 mm.

When the pharmaceutical dosage form according to the invention ismonolithic, it preferably has an extension in any direction of at least2.0 mm, more preferably at least 2.5 mm, still more preferably at least3.0 mm, yet more preferably at least 3.5 mm, even more preferably atleast 4.0 mm, most preferably at least 4.5 mm and in particular at least5.0 mm. Preferably, when the dosage form is monolithic, it has anextension in any direction of more than 2.0 mm.

For the purpose of specification, “in any direction” preferably means inevery direction in the three-dimensional space.

The pharmaceutical dosage form according to the invention may optionallycomprise a coating, e.g. a cosmetic coating. The coating is preferablyapplied after formation of the pharmaceutical dosage form. The coatingmay be applied prior to or after the curing process. The pharmaceuticaldosage forms according to the invention are preferably film coated withconventional film coating compositions. Suitable coating materials arecommercially available, e.g. under the trademarks Opadry® and Eudragit®.

Examples of suitable materials include cellulose esters and celluloseethers, such as methylcellulose (MC), hydroxypropylmethylcellulose(HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC),sodium carboxymethylcellulose (Na-CMC), poly(meth)-acrylates, such asaminoalkylmethacrylate copolymers, methacrylic acid methylmethacrylatecopolymers, methacrylic acid methylmethacrylate copolymers; vinylpolymers, such as polyvinylpyrrolidone, polyvinyl alcohol,polyvinylacetate; and natural film formers.

The coating can be resistant to gastric juices and dissolve as afunction of the pH value of the release environment. By means of thiscoating, it is possible to ensure that the pharmaceutical dosage formaccording to the invention passes through the stomach undissolved andthe active compound is only released in the intestines. The coatingwhich is resistant to gastric juices preferably dissolves at a pH valueof between 5 and 7.5.

The coating can also be applied e.g. to improve the aesthetic impressionand/or the taste of the pharmaceutical dosage forms and the ease withwhich they can be swallowed. Coating the pharmaceutical dosage formsaccording to the invention can also serve other purposes, e.g. improvingstability and shelf-life. Suitable coating formulations comprise a filmforming polymer such as, for example, polyvinyl alcohol or hydroxypropylmethylcellulose, e.g. hypromellose, a plasticizer such as, for example,a glycol, e.g. propylene glycol or polyethylene glycol, an opacifier,such as, for example, titanium dioxide, and a film smoothener, such as,for example, talc. Suitable coating solvents are water as well asorganic solvents. Examples of organic solvents are alcohols, e.g.ethanol or isopropanol, ketones, e.g. acetone, or halogenatedhydrocarbons, e.g. methylene chloride. Coated pharmaceutical dosageforms according to the invention are preferably prepared by first makingthe cores and subsequently coating said cores using conventionaltechniques, such as coating in a coating pan.

Preferably, the pharmaceutical dosage form according to the inventioncomprises a prolonged release matrix.

The prolonged release matrix in turn preferably comprises the EVApolymer as prolonged release matrix material and optionally additionalprolonged release matrix material.

In a preferred embodiment, the prolonged release matrix does not containany additional prolonged release matrix material.

The pharmacologically active ingredient is preferably embedded in theprolonged release matrix comprising the EVA polymer. Preferably, thepharmacologically active ingredient is dispersed in the prolongedrelease matrix.

Preferably, the pharmaceutical dosage form provides prolonged release ofthe pharmacologically active ingredient. Particularly preferably, theprolonged release matrix comprising the EVA polymer provides prolongedrelease of the pharmacologically active ingredient embedded therein.

In a preferred embodiment,

-   (i) the pharmacologically active ingredient is embedded in a    prolonged release matrix comprising the EVA polymer; and/or-   (ii) the pharmaceutical dosage form provides prolonged release of    the pharmacologically active ingredient.

When the pharmaceutical dosage form according to the invention ismonolithic and comprises a prolonged release matrix, the prolongedrelease matrix preferably forms the body of the pharmaceutical dosageform.

When the pharmaceutical dosage form according to the invention ismultiparticulate, e.g. in form of pellets, the particles preferablycomprise the prolonged release matrix and at least a portion of thetotal amount of the pharmacologically active ingredient that iscontained in the pharmaceutical dosage form. Preferably, the particlescomprise the total amount of the pharmacologically active ingredientthat is contained in the pharmaceutical dosage form.

When the pharmaceutical dosage form according to the invention can beregarded as a MUPS formulation which preferably comprisesdrug-containing particles and an outer matrix material, the outer matrixmaterial is not a constituent of the prolonged release matrix and is tobe distinguished from the prolonged release matrix material and theoptionally present additional prolonged release matrix material of theprolonged release matrix of the pharmaceutical dosage form according tothe invention.

For the purpose of specification, the term “particle” refers to adiscrete mass of material that is solid, e.g. at 20° C. or at roomtemperature or ambient temperature. Preferably a particle is solid at20° C. Preferably, the particles are monoliths. Preferably, thepharmacologically active ingredient and the EVA polymer are intimatelyhomogeneously distributed in the particles so that the particles do notcontain any segments where either pharmacologically active ingredient ispresent in the absence of EVA polymer or where EVA polymer is present inthe absence of pharmacologically active ingredient.

When the pharmaceutical dosage form is multiparticulate, it preferablycomprises a multitude i.e. plurality of particles containingpharmacologically active ingredient (drug-containing particles) and mayoptionally further comprise particles not containing anypharmacologically active ingredient (drug-free particles).

In a preferred embodiment, the pharmaceutical dosage form preferablycomprises at most 10, more preferably at most 9, still more preferablyat most 8, yet more preferably at most 7, even more preferably at most6, most preferably at most 5, and in particular at most 4 or 3 or 2drug-containing particles. In another preferred embodiment, thepharmaceutical dosage form preferably comprises at least 2, morepreferably at least 4, still more preferably at least 6, yet morepreferably at least 8, even more preferably at least 10, most preferablyat least 15 and in particular at least 20 or at least 100 or at least1000 drug-containing particles.

When the particles are film coated, the EVA polymer is preferablyhomogeneously distributed in the core of the particles, i.e. the filmcoating preferably does not contain EVA polymer.

When the particles contain a prolonged release matrix and are filmcoated, the prolonged release matrix is preferably homogeneouslydistributed in the core of the particles, i.e. the film coatingpreferably neither contains prolonged release matrix material noroptionally present additional prolonged release matrix material.

The particles are preferably of macroscopic size, typically the averagediameter is within the range of from 100 μm to 2000 μm, preferably 200μm to 1500 μm, more preferably 300 μm to 1500 μm, still more preferably400 μm to 1500 μm, most preferably 500 μm to 1500 μm, and in particular600 μm to 1500 μm. Preferably, the particles in the pharmaceuticaldosage form have an average particle size of at least 50 μm, morepreferably at least 100 μm, still more preferably at least 150 μm or atleast 200 μm, yet more preferably at least 250 μm or at least 300 μm,most preferably at least 400 μm or at least 500 μm, and in particular atleast 550 μm or at least 600 μm. Preferably, the particles in thepharmaceutical dosage form have an average particle size of at least 700μm, more preferably at least 800 μm, most preferably at least 900 μm andin particular at least 1000 μm.

In a preferred embodiment, the pharmaceutical dosage forms according tothe invention comprise particles as a discontinuous phase, i.e. theparticles form a discontinuous phase in an outer matrix material whichin turn preferably forms a continuous phase. In this regard,discontinuous means that not each and every particle is in intimatecontact with another particle but that the particles are at leastpartially separated from one another by the outer matrix material inwhich the particles are embedded. In other words, the particlespreferably do not form a single coherent mass within the pharmaceuticaldosage forms according to the invention.

Preferably, when the pharmaceutical dosage form is multiparticulate, thecontent of the particles in the pharmaceutical dosage forms according tothe invention is at most 95 wt.-%, more preferably at most 90 wt.-%,still more preferably at most 85 wt.-%, yet more preferably at most 80wt.-%, most preferably at most 75 wt.-% and in particular at most 70wt.-%, based on the total weight of the pharmaceutical dosage forms.

Preferably, when the pharmaceutical dosage form is multiparticulate, thecontent of the particles in the pharmaceutical dosage forms according tothe invention is at least 10 wt.-%, at least 15 wt.-%, at least 20 wt.-%or at least 25 wt.-%; more preferably at least 30 wt.-%, at least 35wt.-%, at least 40 wt.-% or at least 45 wt.-%; most preferably at least50 wt.-%, at least 55 wt.-%, at least 60 wt.-% or at least 65 wt.-%; andin particular at least 70 wt.-%, at least 75 wt.-%, at least 80 wt.-% orat least 85 wt.-%; based on the total weight of the pharmaceuticaldosage form.

When the pharmaceutical dosage form is multiparticulate, the shape ofthe particles is not particularly limited. As the particles arepreferably manufactured by hot-melt extrusion, preferred particlespresent in the pharmaceutical dosage forms according to the inventionare generally cylindrical in shape. The diameter of such particles istherefore the diameter of their circular cross section. The cylindricalshape is caused by the extrusion process according to which the diameterof the circular cross section is a function of the extrusion die and thelength of the cylinders is a function of the cutting length according towhich the extruded strand of material is cut into pieces of preferablymore or less predetermined length.

Typically, the aspect ratio is regarded as an important measure of thespherical shape. The aspect ratio is defined as the ratio of the maximaldiameter (d_(max)) and its orthogonal Feret-diameter. For asphericalparticles, the aspect ratio has values above 1. The smaller the valuethe more spherical is the particle. In a preferred embodiment, theaspect ratio of the particles is at most 1.40, more preferably at most1.35, still more preferably at most 1.30, yet more preferably at most1.25, even more preferably at most 1.20, most preferably at most 1.15and in particular at most 1.10. In another preferred embodiment, theaspect ratio of the particles is at least 1.10, more preferably at least1.15, still more preferably at least 1.20, yet more preferably at least1.25, even more preferably at least 1.30, most preferably at least 1.35and in particular at least 1.40.

Preferred particles have an average length and average diameter of about1000 μm or less. When the particles are manufactured by extrusiontechnology, the “length” of particles is the dimension of the particlesthat is parallel to the direction of extrusion. The “diameter” ofparticles is the largest dimension that is perpendicular to thedirection of extrusion.

Particularly preferred particles have an average diameter of less thanabout 2000 μm, more preferably less than about 1000 or 800 μm, stillmore preferably of less than about 650 μm. Especially preferredparticles have an average diameter of less than 700 μm, particularlyless than 600 μm, still more particularly less than 500 μm, e.g. lessthan 400 μm. Particularly preferred particles have an average diameterin the range of 200-1500 μm, more preferably 400-800 μm, still morepreferably 450-700 μm, yet more preferably 500-650 μm, e.g. about500-600 μm. Further preferred particles have an average diameter ofbetween about 300 μm and about 400 μm, of between about 400 μm and 500μm, or of between about 500 μm and 600 μm, or of between 600 μm and 700μm or of between 700 μm and 800 μm.

In a preferred embodiment, particles that are present in thepharmaceutical dosage forms according to the invention have an averagelength in the range of 500 to 5000 μm, more preferably 750 to 4600 μm,still more preferably 1000 to 4200 μm, yet more preferably 1250 to 3800μm, even more preferably 1500 to 3400 μm, most preferably 1750 to 3200μm and in particular 2000 to 3000 μm. According to this embodiment,particles that are present in the pharmaceutical dosage forms accordingto the invention preferably have an average length of less than about4000 μm, more preferably less than about 3000 μm, still more preferablyless than about 2000 μm, e.g. a length of about 1800 μm, about 1600 μmabout 1400 μm, about 1200 μm or about 1000 μm.

In another preferred embodiment, particles that are present in thepharmaceutical dosage forms according to the invention have an averagelength in the range of 200 to 1000 μm, more preferably 400 to 800 μm,still more preferably 450 to 700 μm, yet more preferably 500 to 650 μm,e.g. about 500 to 600 μm. According to this embodiment, particles thatare present in the pharmaceutical dosage forms according to theinvention preferably have an average length of less than about 1000 μm,more preferably less than about 800 μm, still more preferably less thanabout 650 μm, e.g. a length of about 800 μm, about 700 μm about 600 μm,about 500 μm, about 400 μm or about 300 μm. Especially preferredparticles have an average length of less than 700 μm, particularly lessthan 650 μm, still more particularly less than 550 μm, e.g. less than450 μm.

The minimum average length of the particles is determined by the cuttingstep and may be, e.g. 4.0 mm, 3.0 mm, 2.0 mm, 2.5 mm, 2.0 mm, 1.5 mm,1.0 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm or 0.2mm.

In a preferred embodiment, when the pharmaceutical dosage form ismultiparticulate, the individual drug-containing particles have anextension in any direction of at least 2.0 mm, more preferably at least2.2 mm, still more preferably at least 2.5 mm, yet more preferably atleast 2.8 mm, even more preferably at least 3.0 mm, most preferably atleast 3.2 mm, and in particular at least 3.5 mm or 4.0 mm. Preferably,when the dosage form is multiparticulate, the individual drug-containingparticles have an extension in any direction of more than 2.0 mm.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is monolithic and has an extension in any direction ofmore than 2.0 mm; or is multiparticulate, wherein the individualdrug-containing particles have an extension in any direction of morethan 2.0 mm.

Particularly preferably, the pharmaceutical dosage form according to theinvention is monolithic and has an extension in any direction of atleast 2.0 mm; or is multiparticulate, wherein the individualdrug-containing particles have an extension in any direction of at least2.0 mm.

In another preferred embodiment,

-   -   the pharmaceutical dosage form according to the invention is        monolithic and has an extension in any direction of at least 2.5        mm; or is multiparticulate, wherein the individual        drug-containing particles have an extension in any direction of        at least 2.2 mm; or    -   the pharmaceutical dosage form according to the invention is        monolithic and has an extension in any direction of at least 3.0        mm; or is multiparticulate, wherein the individual        drug-containing particles have an extension in any direction of        at least 2.5 mm; or    -   the pharmaceutical dosage form according to the invention is        monolithic and has an extension in any direction of at least 3.5        mm; or is multiparticulate, wherein the individual        drug-containing particles have an extension in any direction of        at least 2.8 mm; or    -   the pharmaceutical dosage form according to the invention is        monolithic and has an extension in any direction of at least 4.0        mm; or is multiparticulate, wherein the individual        drug-containing particles have an extension in any direction of        at least 3.0 mm; or    -   the pharmaceutical dosage form according to the invention is        monolithic and has an extension in any direction of at least 4.5        mm; or is multiparticulate, wherein the individual        drug-containing particles have an extension in any direction of        at least 3.2 mm; or    -   the pharmaceutical dosage form according to the invention is        monolithic and has an extension in any direction of at least 5.0        mm; or is multiparticulate, wherein the individual        drug-containing particles have an extension in any direction of        at least 3.5 mm or at least 4.0 mm.

The size of particles may be determined by any conventional procedureknown in the art, e.g. laser light scattering, sieve analysis, lightmicroscopy or image analysis.

Preferably, when the pharmaceutical dosage form is multiparticulate, theplurality of particles that is contained in the pharmaceutical dosageform according to the invention has an arithmetic average weight, in thefollowing referred to as “aaw”, wherein at least 70%, more preferably atleast 75%, still more preferably at least 80%, yet more preferably atleast 85%, most preferably at least 90% and in particular at least 95%of the individual particles contained in said plurality of particles hasan individual weight within the range of aaw ±30%, more preferably aaw±25%, still more preferably aaw ±20%, yet more preferably aaw ±15%, mostpreferably aaw ±10%, and in particular aaw ±5%. For example, if thepharmaceutical dosage form according to the invention contains aplurality of 100 particles and aaw of said plurality of particles is1.00 mg, at least 75 individual particles (i.e. 75%) have an individualweight within the range of from 0.70 to 1.30 mg (1.00 mg ±30%).

In a preferred embodiment, the particles, more preferably thedrug-containing particles, each have a weight of less than 20 mg, morepreferably less than 18 mg, still more preferably less than 16 mg, yetmore preferably less than 14 mg, even more preferably less than 12 mg orless than 10 mg, most preferably less than 8 mg, and in particular lessthan 6 or 4 mg. According to this embodiment, all individual particleseach preferably have a weight of from 1 to 19 mg, more preferably 1.5 to15 mg, still more preferably 2.0 to 12 mg, yet more preferably 2.2 to 10mg, even more preferably 2.5 to 8 mg, most preferably 2.8 to 6 mg and inparticular 3 to 5 mg.

In another preferred embodiment, the particles, more preferably thedrug-containing particles, each have a weight of 20 mg or more.According to this embodiment, all individual particles preferably eachhave a weight of at least 30 mg, more preferably at least 40 mg, stillmore preferably at least 50 mg, most preferably at least 60 mg and inparticular at least 100 mg. Preferably, all individual particles eachhave a weight of from 20 to 1000 mg, more preferably 30 to 800 mg, stillmore preferably 40 to 600 mg, yet more preferably 50 to 400 mg, evenmore preferably 60 to 200 mg, most preferably 70 to 150 mg and inparticular 80 to 120 mg. According to this embodiment, the particles ofthe pharmaceutical dosage form, more preferably the drug-containingparticles of the pharmaceutical dosage form, preferably each have anextension in any given direction of at least 2.0 mm or 3.0 mm and have aweight of at least 20 mg.

In a preferred embodiment, when the pharmaceutical dosage form ismultiparticulate, the particles are not film coated.

In another preferred embodiment, when the pharmaceutical dosage form ismultiparticulate, the particles are film coated. The particles accordingto the invention can optionally be provided, partially or completely,with a conventional coating. The particles are preferably film coatedwith conventional film coating compositions. Suitable coating materialsare commercially available, e.g. under the trademarks Opadry® andEudragit®.

Examples of suitable materials include cellulose esters and celluloseethers, such as methylcellulose (MC), hydroxypropylmethylcellulose(HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC),sodium carboxymethylcellulose (Na-CMC), ethylcellulose (EC), celluloseacetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP);poly(meth)acrylates, such as aminoalkylmethacrylate copolymers,ethylacrylate methylmethacrylate copolymers, methacrylic acidmethylmethacrylate copolymers, methacrylic acid methylmethacrylatecopolymers; vinyl polymers, such as polyvinylpyrrolidone,polyvinylacetatephthalate, polyvinyl alcohol, polyvinylalcohol-polyethylene glycol graft copolymers, polyvinylacetate; andnatural film formers.

The coating material may contain excipients such as stabilizers (e.g.surfactants such as macrogol cetostearylether, sodium dodecylsulfate,and the like). Suitable excipients of film coating materials are knownto the skilled person.

In a particularly preferred embodiment, the coating is water-soluble.

Though less preferred, the coating can principally be resistant togastric juices and dissolve as a function of the pH value of the releaseenvironment. By means of this coating, it is possible to ensure that thepharmaceutical dosage form according to the invention passes through thestomach undissolved and the active compound is only released in theintestines. The coating which is resistant to gastric juices preferablydissolves at a pH value of between 5 and 7.5. Corresponding materialsand methods for the delayed release of active compounds and for theapplication of coatings which are resistant to gastric juices are knownto the person skilled in the art, for example from “CoatedPharmaceutical dosage forms—Fundamentals, Manufacturing Techniques,Biopharmaceutical Aspects, Test Methods and Raw Materials” by Kurt H.Bauer, K. Lehmann, Hermann P. Osterwald, Rothgang, Gerhart, 1st edition,1998, Medpharm Scientific Publishers.

A particularly preferred coating contains polyvinyl alcohol andoptionally, further excipients such as xanthan gum and/or talcum.

When the pharmaceutical dosage form is multiparticulate, the particlescontain at least a pharmacologically active ingredient havingpsychotropic action and an EVA polymer, preferably a prolonged releasematrix containing the EVA polymer as prolonged release matrix materialand optionally additional prolonged release matrix material. Preferably,however, the particles further contain additional pharmaceuticalexcipients such as antioxidants and plasticizers.

When the pharmaceutical dosage form is multiparticulate, the particlesmay be e.g. loosely contained in a capsule, or the particles may beincorporated into an outer matrix material. From a macroscopicperspective, the outer matrix material preferably forms a continuousphase in which the particles are embedded as discontinuous phase.

Preferably, the outer matrix material is preferably a homogenouscoherent mass, preferably a homogeneous mixture of solid constituents,in which the particles are embedded thereby spatially separating theparticles from one another. While it is possible that the surfaces ofparticles are in contact or at least in very close proximity with oneanother, the plurality of particles preferably cannot be regarded as asingle continuous coherent mass within the pharmaceutical dosage form.

In other words, when the pharmaceutical dosage form is multiparticulateand the particles are contained in an outer matrix material, thepharmaceutical dosage form according to the invention preferablycomprises the particles as volume element(s) of a first type in whichthe pharmacologically active ingredient and the EVA polymer arecontained, and the outer matrix material as volume element of a secondtype differing from the material that forms the particles, preferablycontaining neither pharmacologically active ingredient nor EVA polymer.

When the pharmaceutical dosage form is multiparticulate and theparticles are contained in an outer matrix material, the relative weightratio of particles to outer matrix material is not particularly limited.Preferably, said relative weight ratio is within the range of1:1.00±0.75, more preferably 1:1.00±0.50, still more preferably1:1.00±0.40, yet more preferably 1:1.00±0.30, most preferably1:1.00±0.20, and in particular 1:1.00±0.10.

Preferably, the content of the outer matrix material is at least 2.5wt.-%, at least 5 wt.-%, at least 7.5 wt.-% or at least 10 wt.-%; atleast 12.5 wt.-%, at least 15 wt.-%, at least 17.5 wt.-% or at least 20wt.-%; at least 22.5 wt.-%, at least 25 wt.-%, at least 27.5 wt.-% or atleast 30 wt.-%; at least 32.5 wt.-%, at least 35 wt.-%, at least 37.5wt.-% or at least 40 wt.-%; more preferably at least 42.5 wt.-%, atleast 45 wt.-%, at least 47.5 wt.-% or at least 50 wt.-%; still morepreferably at least 52.5 wt.-%, at least 55 wt.-%, at least 57.5 wt.-%or at least 60 wt.-%; yet more preferably at least 62.5 wt.-%, at least65 wt.-%, at least 67.5 wt.-% or at least 60 wt.-%; most preferably atleast 72.5 wt.-%, at least 75 wt.-%, at least 77.5 wt.-% or at least 70wt.-%; and in particular at least 82.5 wt.-%, at least 85 wt.-%, atleast 87.5 wt.-% or at least 90 wt.-%; based on the total weight of thepharmaceutical dosage form.

Preferably, the content of the outer matrix material is at most 90wt.-%, at most 87.5 wt.-%, at most 85 wt.-%, or at most 82.5 wt.-%; morepreferably at most 80 wt.-%, at most 77.5 wt.-%, at most 75 wt.-% or atmost 72.5 wt.-%; still more preferably at most 70 wt.-%, at most 67.5wt.-%, at most 65 wt.-% or at most 62.5 wt.-%; yet more preferably atmost 60 wt.-%, at most 57.5 wt.-%, at most 55 wt.-% or at most 52.5wt.-%; most preferably at most 50 wt.-%, at most 47.5 wt.-%, at most 45wt.-% or at most 42.5 wt.-%; and in particular at most 40 wt.-%, at most37.5 wt.-%, or at most 35 wt.-%; based on the total weight of thepharmaceutical dosage form.

Preferably, the outer matrix material is a mixture, preferably ahomogeneous mixture of at least two different constituents, morepreferably of at least three different constituents. In a preferredembodiment, all constituents of the outer matrix material arehomogeneously distributed in the continuous phase that is formed by theouter matrix material.

Preferably, the outer matrix material is also provided in particulateform, i.e. in the course of the manufacture of the pharmaceutical dosageforms according to the invention, the constituents of the outer matrixmaterial are preferably processed into particles, subsequently mixedwith the particles that contain the pharmacologically active ingredientand the EVA polymer, and then compressed into the pharmaceutical dosageforms.

Preferably, the average size of the particles of the outer matrixmaterial is within the range of ±60%, more preferably ±50%, still morepreferably ±40%, yet more preferably ±30%, most preferably ±20%, and inparticular ±10% of the average size of the particles that contain thepharmacologically active ingredient and the EVA polymer.

The particles of the outer matrix material can be manufactured byconventional methods for the preparation of aggregates and agglomeratesfrom powder mixtures such as granulating and compacting.

In a preferred embodiment, the mixture of all constituents of the outermatrix material is blended and pre-compacted thereby yielding apre-compacted outer matrix material.

The outer matrix material preferably does not contain anypharmacologically active ingredient.

Preferably, the outer matrix material comprises a filler or a binder. Asmany fillers can be regarded as binders and vice versa, for the purposeof specification “filler/binder” refers to any excipient that issuitable as filler, binder or both. Thus, the outer matrix materialpreferably comprises a filler/binder.

Preferred fillers (=filler/binders) are selected from the groupconsisting of silicium dioxide (e.g. Aerosil®), microcrystallinecellulose (e.g. Avicel®, Elcema®, Emocel®, ExCel®, Vitacell®; celluloseether (e.g. Natrosol®, Klucel®, Methocel®, Blanose®, Pharmacoat®,Viscontran®); mannitol; dextrines; dextrose; calciumhydrogen phosphate(e.g. Emcompress®); maltodextrine (e.g. Emdex®); lactose (e.g. Fast-FlowLactose®; Ludipress® Pharmaceutical dosage Formtose®, Zeparox®);polyvinylpyrrolidone (PVP) (e.g. Kollidone®, Polyplasdone®, Polydone®);saccharose (e.g. Nu-Tab®, Sugar Tab®); magnesium salts (e.g. MgCO₃, MgO,MgSiO₃); starches and pretreated starches (e.g. Prejel®, Primotab® ET,Starch® 1500). Preferred binders are selected from the group consistingof alginates; chitosanes; and any of the fillers mentioned above(=fillers/binders).

Some fillers/binders may also serve other purposes. It is known, forexample, that silicium dioxide exhibits excellent function as a glidant.Thus, preferably, the outer matrix material comprises a glidant such assilicium dioxide.

In a preferred embodiment, the content of the filler/binder or mixtureof fillers/binders in the outer matrix material is within the range of50±25 wt.-%, more preferably 50±20 wt.-%, still more preferably 50±15wt.-%, yet more preferably 50±10 wt.-%, most preferably 50±7.5 wt.-%,and in particular 50±5 wt.-%, based on the total weight of outer matrixmaterial. In another preferred embodiment, the content of thefiller/binder or mixture of fillers/binders in the outer matrix materialis within the range of 65±25 wt.-%, more preferably 65±20 wt.-%, stillmore preferably 65±15 wt.-%, yet more preferably 65±10 wt.-%, mostpreferably 65±7.5 wt.-%, and in particular 65±5 wt.-%, based on thetotal weight of outer matrix material. In still another preferredembodiment, the content of the filler/binder or mixture offillers/binders in the outer matrix material is within the range of80±19 wt.-%, more preferably 80±17.5 wt.-%, still more preferably 80±15wt.-%, yet more preferably 80±10 wt.-%, most preferably 80±7.5 wt.-%,and in particular 80±5 wt.-%, based on the total weight of outer matrixmaterial. In another preferred embodiment, the content of thefiller/binder or mixture of fillers/binders in the outer matrix materialis within the range of 90±9 wt.-%, more preferably 90±8 wt.-%, stillmore preferably 90±7 wt.-%, yet more preferably 90±6 wt.-%, mostpreferably 90±5 wt.-%, and in particular 90±4 wt.-%, based on the totalweight of outer matrix material.

In a preferred embodiment, the content of the filler/binder or mixtureof fillers/binders in the pharmaceutical dosage form is within the rangeof 25±24 wt.-%, more preferably 25±20 wt.-%, still more preferably 25±16wt.-%, yet more preferably 25±12 wt.-%, most preferably 25±8 wt.-%, andin particular 25±4 wt.-%, based on the total weight of pharmaceuticaldosage form. In another preferred embodiment, the content of thefiller/binder or mixture of fillers/binders in the pharmaceutical dosageform is within the range of 30±29 wt.-%, more preferably 30±25 wt.-%,still more preferably 30±20 wt.-%, yet more preferably 30±15 wt.-%, mostpreferably 30±10 wt.-%, and in particular 30±5 wt.-%, based on the totalweight of pharmaceutical dosage form. In still another preferredembodiment, the content of the filler/binder or mixture offillers/binders in the pharmaceutical dosage form is within the range of35±34 wt.-%, more preferably 35±28 wt.-%, still more preferably 35±22wt.-%, yet more preferably 35±16 wt.-%, most preferably 35±10 wt.-%, andin particular 35±4 wt.-%, based on the total weight of pharmaceuticaldosage form. In another preferred embodiment, the content of thefiller/binder or mixture of fillers/binders in the pharmaceutical dosageform is within the range of 40±39 wt.-%, more preferably 40±32 wt.-%,still more preferably 40±25 wt.-%, yet more preferably 40±18 wt.-%, mostpreferably 40±11 wt.-%, and in particular 40±4 wt.-%, based on the totalweight of pharmaceutical dosage form.

Preferably, the filler/binder is contained in the outer matrix materialbut not in the drug-containing particles of the pharmaceutical dosageform according to the invention.

Preferably, the outer matrix material comprises a diluent or lubricant,preferably selected from the group consisting of calcium stearate;magnesium stearate; glycerol monobehenate (e.g. Compritol®); Myvatex®;Precirol®; Precirol® Ato5; sodium stearylfumarate (e.g. Pruv®); andtalcum. Magnesium stearate is particularly preferred. Preferably, thecontent of the lubricant in the outer matrix material is at most 10.0wt.-%, more preferably at most 7.5 wt.-%, still more preferably at most5.0 wt.-%, yet more preferably at most 2.0 wt.-%, even more preferablyat most 1.0 wt.-%, and most preferably at most 0.5 wt.-%, based on thetotal weight of the outer matrix material and based on the total weightof pharmaceutical dosage form.

In particularly preferred embodiment, the outer matrix materialcomprises a combination of filler/binder and lubricant.

The outer matrix material of the pharmaceutical dosage forms accordingto the invention may additionally contain other excipients that areconventional in the art, e.g. diluents, binders, granulating aids,colorants, flavor additives, glidants, wet-regulating agents anddisintegrants. The skilled person will readily be able to determineappropriate quantities of each of these excipients.

In a preferred embodiment, however, the outer matrix material of thepharmaceutical dosage form according to the invention consists of one ormore disintegrants, one or more filler/binder's and one or morelubricants, but does not contain any other constituents.

In a particularly preferred embodiment, the outer matrix material of thepharmaceutical dosage form according to the invention does not containone or more gel-forming agents and/or a silicone.

As used herein the term “gel-forming agent” is used to refer to acompound that, upon contact with a solvent (e.g. water), absorbs thesolvent and swells, thereby forming a viscous or semi-viscous substance.Preferred gel-forming agents are not cross-linked. This substance maymoderate pharmacologically active ingredient release from the embeddedparticles in both aqueous and aqueous alcoholic media. Upon fullhydration, a thick viscous solution or dispersion is typically producedthat significantly reduces and/or minimizes the amount of free solventwhich can contain an amount of solubilized pharmacologically activeingredient, and which can be drawn into a syringe. The gel that isformed may also reduce the overall amount of pharmacologically activeingredient extractable with the solvent by entrapping thepharmacologically active ingredient within a gel structure. Thus thegel-forming agent may play an important role in conferringtamper-resistance to the pharmaceutical dosage forms according to theinvention.

Gel-forming agents that preferably are not contained in the outer matrixmaterial include pharmaceutically acceptable polymers, typicallyhydrophilic polymers, such as hydrogels. Representative examples ofgel-forming agent include polyalkylene oxide such as polyethylene oxide,polyvinyl alcohol, hydroxypropylmethyl cellulose, carbomers,poly(uronic) acids and mixtures thereof.

When the pharmaceutical dosage form comprises a prolonged release matrixin which the pharmacologically active ingredient is embedded,preferably, the overall content of the prolonged release matrix, i.e. ofthe prolonged release matrix material and the optionally presentadditional prolonged release matrix material, is within the range offrom 5 to 95 wt.-%, more preferably 15 to 90 wt.-%, still morepreferably 25 to 88 wt.-%, yet more preferably 35 to 86 wt.-%, even morepreferably 45 to 84 wt.-%, most preferably 55 to 82 wt.-% and inparticular 60 to 80 wt.-%, relative to the total weight of thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, based on the total weight of the particles thatcontain the pharmacologically active ingredient.

In a preferred embodiment, the content of the prolonged release matrixis at least 20 wt.-%, more preferably at least 30 wt.-%, still morepreferably at least 40 wt.-%, yet more preferably at least 50 wt.-% andin particular at least 60 wt.-%, either based on the total weight of thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, based on the total weight of the particles thatcontain the pharmacologically active ingredient.

In a preferred embodiment, the overall content of prolonged releasematrix is within the range of 30±20 wt.-%, more preferably 30±15 wt.-%,most preferably 30±10 wt.-%, and in particular 30±5 wt.-%, either basedon the total weight of the pharmaceutical dosage form or, when thepharmaceutical dosage form is multiparticulate, based on the totalweight of the particles that contain the pharmacologically activeingredient.

In another preferred embodiment, the overall content of prolongedrelease matrix is within the range of 35±20 wt.-%, more preferably 35±15wt.-%, most preferably 35±10 wt.-%, and in particular 35±5 wt.-%, eitherbased on the total weight of the pharmaceutical dosage form or, when thepharmaceutical dosage form is multiparticulate, based on the totalweight of the particles that contain the pharmacologically activeingredient.

In still another preferred embodiment, the overall content of prolongedrelease matrix is within the range of 40±20 wt.-%, more preferably 40±15wt.-%, and most preferably 40±10 wt.-%, and in particular 40±5 wt.-%,either based on the total weight of the pharmaceutical dosage form or,when the pharmaceutical dosage form is multiparticulate, based on thetotal weight of the particles that contain the pharmacologically activeingredient.

In yet another preferred embodiment, the overall content of prolongedrelease matrix is within the range of 45±20 wt.-%, more preferably 45±15wt.-%, and most preferably 45±10 wt.-%, and in particular 45±5 wt.-%,either based on the total weight of the pharmaceutical dosage form or,when the pharmaceutical dosage form is multiparticulate, based on thetotal weight of the particles that contain the pharmacologically activeingredient.

In even another preferred embodiment, the overall content of prolongedrelease matrix is within the range of 50±20 wt.-%, more preferably 50±15wt.-%, and most preferably 50±10 wt.-%, and in particular 50±5 wt.-%,either based on the total weight of the pharmaceutical dosage form or,when the pharmaceutical dosage form is multiparticulate, based on thetotal weight of the particles that contain the pharmacologically activeingredient.

In a further preferred embodiment, the overall content of prolongedrelease matrix is within the range of 55±20 wt.-%, more preferably 55±15wt.-%, and most preferably 55±10 wt.-%, and in particular 55±5 wt.-%,either based on the total weight of the pharmaceutical dosage form or,when the pharmaceutical dosage form is multiparticulate, based on thetotal weight of the particles that contain the pharmacologically activeingredient.

In still a further preferred embodiment, the overall content ofprolonged release matrix is within the range of 60±20 wt.-%, morepreferably 60±15 wt.-%, and most preferably 60±10 wt.-%, and inparticular 60±5 wt.-%, either based on the total weight of thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, based on the total weight of the particles thatcontain the pharmacologically active ingredient.

In yet a further preferred embodiment, the overall content of prolongedrelease matrix is within the range of 65±20 wt.-%, more preferably 65±15wt.-%, and most preferably 65±10 wt.-%, and in particular 65±5 wt.-%,either based on the total weight of the pharmaceutical dosage form or,when the pharmaceutical dosage form is multiparticulate, based on thetotal weight of the particles that contain the pharmacologically activeingredient.

In even a further preferred embodiment, the overall content of prolongedrelease matrix is within the range of 70±20 wt.-%, more preferably 70±15wt.-%, and most preferably 70±10 wt.-%, and in particular 70±5 wt.-%,either based on the total weight of the pharmaceutical dosage form or,when the pharmaceutical dosage form is multiparticulate, based on thetotal weight of the particles that contain the pharmacologically activeingredient.

In another further preferred embodiment, the overall content ofprolonged release matrix is within the range of 75±20 wt.-%, morepreferably 75±15 wt.-%, and most preferably 75±10 wt.-%, and inparticular 75±5 wt.-%, either based on the total weight of thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, based on the total weight of the particles thatcontain the pharmacologically active ingredient.

In still another preferred embodiment, the overall content of prolongedrelease matrix is within the range of 80±20 wt.-%, more preferably 80±15wt.-%, and most preferably 80±10 wt.-%, and in particular 80±5 wt.-%,either based on the total weight of the pharmaceutical dosage form or,when the pharmaceutical dosage form is multiparticulate, based on thetotal weight of the particles that contain the pharmacologically activeingredient.

Preferably, the relative weight ratio of the prolonged release matrix tothe pharmacologically active ingredient is within the range of 20:1 to1:20, more preferably 15:1 to 1:15, still more preferably 10:1 to 1:10,yet more preferably 7:1 to 1:7, most preferably 5:1 to 1:5, and inparticular 3:1 to 1:1.

Irrespective of whether the pharmaceutical dosage form ismultiparticulate or not, the pharmaceutical dosage form according to theinvention comprises a pharmacologically active ingredient havingpsychotropic action and an EVA polymer.

Particularly preferably, the pharmaceutical dosage form according to theinvention comprises a prolonged release matrix containing the EVApolymer as prolonged release matrix material in which thepharmacologically active ingredient is embedded.

Preferably, the EVA polymer is obtainable by polymerizing a mixturecontaining ethylene and vinyl acetate. Subsequent to the polymerizationreaction, the acetate groups of the vinyl acetate contained in the EVApolymer may optionally be subjected to a partial or completehydrolyzation yielding hydroxy groups.

In a preferred embodiment, the EVA polymer comprises repetition unitsderived from ethylene and vinyl acetate and/or vinyl alcohol.

According to this embodiment, the EVA polymer may comprise repetitionunits derived from

(i) ethylene and vinyl acetate; or

(ii) ethylene and vinyl alcohol; or

(ii) ethylene, vinyl acetate and vinyl alcohol.

Embodiments (i) and (iii) are particularly preferred.

Preferably, the relative molar content of the ethylene repetition unitswithin the EVA polymer is greater than the relative molar content of thevinyl acetate repetition units and/or the vinyl alcohol repetition unitswithin the EVA polymer.

Preferably, the EVA polymer contains at least 10 wt.-%, more preferablyat least 20 wt.-%, still more preferably at least 25 wt.-%, yet morepreferably at least 30 wt.-%, even more preferably at least 35 wt.-%,most preferably at least 40 wt.-% and in particular at least 45 wt.-% ofethylene repetition units, relative to the total weight of the EVApolymer.

Particularly preferably, the EVA polymer contains at least 50 wt.-%,more preferably at least 52 wt.-%, still more preferably at least 54wt.-%, yet more preferably at least 55 wt.-%, even more preferably atleast 56 wt.-%, most preferably at least 57 wt.-% and in particular atleast 58 wt.-% of ethylene repetition units, relative to the totalweight of the EVA polymer.

In another preferred embodiment, the EVA polymer contains at least 60wt.-%, more preferably at least 62 wt.-%, still more preferably at least64 wt.-%, yet more preferably at least 66 wt.-%, even more preferably atleast 68 wt.-%, most preferably at least 69 wt.-% and in particular atleast 70 wt.-% of ethylene repetition units, relative to the totalweight of the EVA polymer.

In still another preferred embodiment, the EVA polymer contains at least72 wt.-%, more preferably at least 75 wt.-%, still more preferably atleast 78 wt.-%, yet more preferably at least 80 wt.-%, even morepreferably at least 82 wt.-%, most preferably at least 84 wt.-% and inparticular at least 86 wt.-% of ethylene repetition units, relative tothe total weight of the EVA polymer.

Preferably, the EVA polymer contains from 30 to 99 wt.-% of ethylenerepetition units, relative to the total weight of the EVA polymer.

Particularly preferably, the EVA polymer contains from 50 to 95 wt.-% ofethylene repetition units, relative to the total weight of the EVApolymer.

In a preferred embodiment, the EVA polymer contains 30±25 wt.-%, morepreferably 30±20 wt.-%, still more preferably 30±17 wt.-%, yet morepreferably 30±13 wt.-%, even more preferably 30±10 wt.-%, mostpreferably 30±7 wt.-% and in particular 30±5 wt.-% of ethylenerepetition units, relative to the total weight of the EVA polymer.

In another preferred embodiment, the EVA polymer contains 40±35 wt.-%,more preferably 40±30 wt.-%, still more preferably 40±25 wt.-%, yet morepreferably 40±20 wt.-%, even more preferably 40±15 wt.-%, mostpreferably 40±10 wt.-% and in particular 40±5 wt.-% of ethylenerepetition units, relative to the total weight of the EVA polymer.

In still another preferred embodiment, the EVA polymer contains 50±45wt.-%, more preferably 50±35 wt.-%, still more preferably 50±25 wt.-%,yet more preferably 50±20 wt.-%, even more preferably 50±15 wt.-%, mostpreferably 50±10 wt.-% and in particular 50±5 wt.-% of ethylenerepetition units, relative to the total weight of the EVA polymer.

In yet another preferred embodiment, the EVA polymer contains 60±35wt.-%, more preferably 60±30 wt.-%, still more preferably 60±25 wt.-%,yet more preferably 60±20 wt.-%, even more preferably 60±15 wt.-%, mostpreferably 60±10 wt.-% and in particular 60±5 wt.-% of ethylenerepetition units, relative to the total weight of the EVA polymer.

In a further preferred embodiment, the EVA polymer contains 70±25 wt.-%,more preferably 70±20 wt.-%, still more preferably 70±17 wt.-%, yet morepreferably 70±13 wt.-%, even more preferably 70±10 wt.-%, mostpreferably 70±7 wt.-% and in particular 70±5 wt.-% of ethylenerepetition units, relative to the total weight of the EVA polymer.

In still a further preferred embodiment, the EVA polymer contains 80±15wt.-%, more preferably 80±12 wt.-%, still more preferably 80±10 wt.-%,yet more preferably 80±8 wt.-%, even more preferably 80±6 wt.-%, mostpreferably 80±4 wt.-% and in particular 80±2 wt.-% of ethylenerepetition units, relative to the total weight of the EVA polymer.

In yet a further preferred embodiment, the EVA polymer contains 90±15wt.-%, more preferably 90±12 wt.-%, still more preferably 90±10 wt.-%,yet more preferably 90±8 wt.-%, even more preferably 90±6 wt.-%, mostpreferably 90±4 wt.-% and in particular 90±2 wt.-% of ethylenerepetition units, relative to the total weight of the EVA polymer.

In a particularly preferred embodiment, the EVA polymer contains 60±5wt.-% of ethylene repetition units, relative to the total weight of theEVA polymer.

Preferably, the molar ratio of the vinyl acetate repetition units to thevinyl alcohol repetition units is within the range of from 1000:1 to1:1000, more preferably from 900:1 to 1:900, still more preferably from500:1 to 1:500, yet more preferably from 300:1 to 1:100, even morepreferably from 200:1 to 1:10, most preferably from 100:1 to 10:1, andin particular about 100:1.

In a preferred embodiment, the EVA polymer has a melt flow rate at 190°C. and 2.16 kg of at least 1 g/10 min, more preferably at least 2 g/10min, still more preferably at least 2.5 g/10 min, yet more preferably atleast 5 g/10 min, even more preferably at least 10 g/10 min, mostpreferably at least 20 g/10 min and in particular at least 30 g/10 minmeasured according to ASTM D1238.

In a preferred embodiment, the EVA polymer has a melt flow rate at 190°C. and 2.16 kg of at least 40 g/10 min, more preferably at least 42 g/10min, still more preferably at least 44 g/10 min, yet more preferably atleast 46 g/10 min, even more preferably at least 48 g/10 min, mostpreferably at least 49 g/10 min and in particular at least 50 g/10 minmeasured according to ASTM D1238.

In another preferred embodiment, the EVA polymer has a melt flow rate at190° C. and 2.16 kg of at least 55 g/10 min, more preferably at least 70g/10 min, still more preferably at least 85 g/10 min, yet morepreferably at least 100 g/10 min, even more preferably at least 115 g/10min, most preferably at least 130 g/10 min and in particular at least140 g/10 min measured according to ASTM D1238.

Preferably, the EVA polymer has a melt flow rate at 190° C. and 2.16 kgwithin the range of from 1 to 160 g/10 min measured according to ASTMD1238.

In a preferred embodiment, the EVA polymer has a melt flow rate at 190°C. and 2.16 kg of 2.5±2 g/10 min, more preferably 2.5±1.5 g/10 min,still more preferably 2.5±1.0 g/10 min, yet more preferably 2.5±0.8 g/10min, even more preferably 2.5±0.6 g/10 min, most preferably 2.5±0.4 g/10min and in particular 2.5±0.2 g/10 min measured according to ASTM D1238.

In another preferred embodiment, the EVA polymer has a melt flow rate at190° C. and 2.16 kg of 3±2 g/10 min, more preferably 3±1.5 g/10 min,still more preferably 3±1.0 g/10 min, yet more preferably 3±0.8 g/10min, even more preferably 3±0.6 g/10 min, most preferably 3±0.4 g/10 minand in particular 3±0.2 g/10 min measured according to ASTM D1238.

In still another preferred embodiment, the EVA polymer has a melt flowrate at 190° C. and 2.16 kg of 10±16 g/10 min, more preferably 10±14g/10 min, still more preferably 10±12 g/10 min, yet more preferably10±10 g/10 min, even more preferably 10±8 g/10 min, most preferably 10±6g/10 min and in particular 10±4 g/10 min measured according to ASTMD1238.

In yet another preferred embodiment, the EVA polymer has a melt flowrate at 190° C. and 2.16 kg of 20±15 g/10 min, more preferably 20±13g/10 min, still more preferably 20±11 g/10 min, yet more preferably 20±9g/10 min, even more preferably 20±7 g/10 min, most preferably 20±5 g/10min and in particular 20±4 g/10 min measured according to ASTM D1238.

In even another preferred embodiment, the EVA polymer has a melt flowrate at 190° C. and 2.16 kg of 30±25 g/10 min, more preferably 30±20g/10 min, still more preferably 30±16 g/10 min, yet more preferably30±13 g/10 min, even more preferably 30±10 g/10 min, most preferably30±7 g/10 min and in particular 30±5 g/10 min measured according to ASTMD1238.

In a further preferred embodiment, the EVA polymer has a melt flow rateat 190° C. and 2.16 kg of 40±35 g/10 min, more preferably 40±25 g/10min, still more preferably 40±15 g/10 min, yet more preferably 40±13g/10 min, even more preferably 40±10 g/10 min, most preferably 40±7 g/10min and in particular 40±5 g/10 min measured according to ASTM D1238.

In still a further preferred embodiment, the EVA polymer has a melt flowrate at 190° C. and 2.16 kg of 52±20 g/10 min, more preferably 52±16g/10 min, still more preferably 52±13 g/10 min, yet more preferably52±10 g/10 min, even more preferably 52±7 g/10 min, most preferably 52±5g/10 min and in particular 52±2 g/10 min measured according to ASTMD1238.

In yet a further preferred embodiment, the EVA polymer has a melt flowrate at 190° C. and 2.16 kg of 60±35 g/10 min, more preferably 60±25g/10 min, still more preferably 60±15 g/10 min, yet more preferably60±13 g/10 min, even more preferably 60±10 g/10 min, most preferably60±7 g/10 min and in particular 60±5 g/10 min measured according to ASTMD1238.

In even a further preferred embodiment, the EVA polymer has a melt flowrate at 190° C. and 2.16 kg of 80±35 g/10 min, more preferably 80±25g/10 min, still more preferably 80±15 g/10 min, yet more preferably80±13 g/10 min, even more preferably 80±10 g/10 min, most preferably80±7 g/10 min and in particular 80±5 g/10 min measured according to ASTMD1238.

In another preferred embodiment, the EVA polymer has a melt flow rate at190° C. and 2.16 kg of 100±35 g/10 min, more preferably 100±25 g/10 min,still more preferably 100±15 g/10 min, yet more preferably 100±13 g/10min, even more preferably 100±10 g/10 min, most preferably 100±7 g/10min and in particular 100±5 g/10 min measured according to ASTM D1238.

In still another preferred embodiment, the EVA polymer has a melt flowrate at 190° C. and 2.16 kg of 125±35 g/10 min, more preferably 125±25g/10 min, still more preferably 125±15 g/10 min, yet more preferably125±13 g/10 min, even more preferably 125±10 g/10 min, most preferably125±7 g/10 min and in particular 125±5 g/10 min measured according toASTM D1238.

In yet another preferred embodiment, the EVA polymer has a melt flowrate at 190° C. and 2.16 kg of 150±35 g/10 min, more preferably 150±25g/10 min, still more preferably 150±15 g/10 min, yet more preferably150±13 g/10 min, even more preferably 150±10 g/10 min, most preferably150±7 g/10 min and in particular 150±5 g/10 min measured according toASTM D1238.

In a particularly preferred embodiment, the EVA polymer has a melt flowrate at 190° C. and 2.16 kg of 52±2 g/10 min measured according to ASTMD1238.

The EVA polymer may comprise a single EVA polymer having a particularmelt flow rate, or a mixture (blend) of different EVA polymers, such astwo, three, four or five EVA polymers, e.g., EVA polymers of the samechemical nature but different melt flow rates, EVA polymers of differentchemical nature but same melt flow rates, or EVA polymers of differentchemical nature as well as different melt flow rates.

In a preferred embodiment, the EVA polymer comprises a single EVApolymer having a particular melt flow rate. According to thisembodiment, the EVA preferably comprises a single EVA polymer having amelt flow rate at 190° C. and 2.16 kg of 52±2 g/10 min measuredaccording to ASTM D1238 and preferably containing 60±5 wt.-% of ethylenerepetition units, relative to the total weight of the EVA polymer.

The EVA polymer preferably has a melting point in the range of 40 to100° C., determined via differential scanning calorimetry (DSC) inaccordance with ASTM D3418.

In a preferred embodiment, the EVA polymer has a melting point of 40±10°C., 47±10° C., 52±10° C., 58±10° C., 65±10° C., 70±10° C., 80±10° C.,90±10° C. or 96±10° C., more preferably 40±5° C., 47±5° C., 52±5° C.,58±5° C., 65±5° C., 70±5° C., 80±5° C., 90±5° C. or 96±5° C., determinedvia differential scanning calorimetry (DSC) in accordance with ASTMD3418.

The EVA polymer preferably has a freezing point in the range of 20 to80° C., determined via DSC in accordance with ASTM D3418.

In a preferred embodiment, the EVA polymer has a freezing point of20±10° C., 27±10° C., 30±10° C., 35±10° C., 40±10° C., 49±10° C., 60±10°C., 70±10° C. or 74±10° C., more preferably 20±5° C., 27±5° C., 30±5°C., 35±5° C., 40±5° C., 49±5° C., 60±5° C., 70±5° C. or 74±° C.,determined via DSC in accordance with ASTM D3418.

Particularly preferably, the EVA polymer has a melting point of 47±5° C.and a freezing point of 27±5° C., both determined via DSC in accordancewith ASTM D3418

In a preferred embodiment, the EVA polymer is homogeneously distributedin the pharmaceutical dosage form according to the invention.

When the pharmaceutical dosage form is multiparticulate, the EVA polymeris preferably homogeneously distributed in the particles according tothe invention that contain the pharmacologically active ingredient.Preferably, the pharmacologically active ingredient and the EVA polymerare intimately homogeneously distributed in the pharmaceutical dosageform and the particles, respectively, so that the pharmaceutical dosageform and the particles, respectively, do not contain any segments whereeither pharmacologically active ingredient is present in the absence ofEVA polymer or where EVA polymer is present in the absence ofpharmacologically active ingredient.

When the pharmaceutical dosage form and the particles, respectively, arefilm coated, the EVA polymer is preferably homogeneously distributed inthe core of the pharmaceutical dosage form and the particles,respectively, i.e. the film coating preferably does not contain EVApolymer. Nonetheless, the film coating as such may of course contain oneor more polymers, which however, preferably differ from the EVA polymercontained in the core.

EVA polymers that are suitable for use in the pharmaceutical dosageforms according to the invention are commercially available, e.g. fromCelanese, for example Ateva® 1081, Ateva® 1070, Ateva® 1075A, Ateva®1221, Ateva® 11231, Ateva® 1241, Ateva® 1615, Ateva® 1641, Ateva® 1608,Ateva® 1609, Ateva® 1811, Ateva® 1813, Ateva® 1820, Ateva® 1821A, Ateva®1850A, Ateva® 1880A, Ateva® 1941, Ateva® 2005A, Ateva® 2030, Ateva®2020, Ateva® 2604A, Ateva® 2810A, Ateva® 2861A, Ateva® 9020, Ateva®2820A, Ateva® 2821A, Ateva® 9021A, Ateva® 2825A, Ateva® 2830A, Ateva®2842A, Ateva® 2842AC, Ateva® 2850A, Ateva® 9030, Ateva® 3325A, Ateva®3325AC, Ateva® 4030AC, VitalDose® EVA; and from DuPont, for example,Elvax® 40W, Elvax® 220W, Elvax® 265, Elvax® 40L-03, Elvax® 660, Elvax®150, Elvax® 150W, Elvax® 210W, Elvax® 240W, Elvax® 250, Elvax® 260,Elvax® 350, Elvax® 360, Elvax® 410, Elvax® 420, Elvax® 440, Elvax® 450,Elvax® 460, Elvax® 470, Elvax® 550, Elvax® 560, Elvax® 650Q, Elvax® 670,Elvax® 750, Elvax® 760, Elvax® 760Q, Elvax® 770. Preferred polymers areElvax® 40W, Elvax® 220W, Elvax® 265, Elvax® 40L-03 and Elvax® 660. Fordetails concerning the properties of these products, it can be referredto e.g. the product specification.

The content of the EVA polymer is preferably within the range of from5.0 to 95 wt.-%, more preferably 7 to 94 wt.-%, still more preferably 9to 93 wt.-%, yet more preferably 11 to 92 wt.-%, most preferably 13 to91 wt.-%, and in particular 15 to 90 wt.-%, relative to the total weightof the pharmaceutical dosage form. When the pharmaceutical dosage formis multiparticulate, these percent values preferably are related to thetotal weight of the particles, not to the total weight of thepharmaceutical dosage form.

In a particularly preferred embodiment, the content of the EVA polymeris within the range of from 20 to 80 wt.-%, more preferably 25 to 78wt.-%, still more preferably 30 to 76 wt.-%, yet more preferably 35 to74 wt.-%, most preferably 40 to 72 wt.-% and in particular 45 to 70wt.-%, relative to the total weight of the pharmaceutical dosage formor, when the pharmaceutical dosage form is multiparticulate, relative tothe total weight of the particles that contain the pharmacologicallyactive ingredient.

In a preferred embodiment, the content of the EVA polymer is at least 2wt.-%, more preferably at least 5 wt.-%, still more preferably at least10 wt.-%, yet more preferably at least 15 wt.-% and in particular atleast 20 wt.-%, relative to the total weight of the pharmaceuticaldosage form or, when the pharmaceutical dosage form is multiparticulate,relative to the total weight of the particles that contain thepharmacologically active ingredient.

In another preferred embodiment, the content of the EVA polymer is atleast 30 wt.-%, more preferably at least 35 wt.-%, still more preferablyat least 40 wt.-%, yet more preferably at least 45 wt.-%, even morepreferably at least 50, most preferably at least 55 wt.-% and inparticular at least 60 wt.-%, relative to the total weight of thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, relative to the total weight of the particles thatcontain the pharmacologically active ingredient.

In a preferred embodiment, the content of the EVA polymer is 20±15wt.-%, more preferably 20±12 wt.-%, still more preferably 20±10 wt.-%,yet more preferably 20±8 wt.-%, even more preferably 20±6 wt.-%, mostpreferably 20±4 wt.-% and in particular 20±2 wt.-%, relative to thetotal weight of the pharmaceutical dosage form or, when thepharmaceutical dosage form is multiparticulate, relative to the totalweight of the particles that contain the pharmacologically activeingredient.

In another preferred embodiment, the content of the EVA polymer is 30±25wt.-%, more preferably 30±20 wt.-%, still more preferably 30±17 wt.-%,yet more preferably 30±13 wt.-%, even more preferably 30±10 wt.-%, mostpreferably 30±7 wt.-% and in particular 30±5 wt.-%, relative to thetotal weight of the pharmaceutical dosage form or, when thepharmaceutical dosage form is multiparticulate, relative to the totalweight of the particles that contain the pharmacologically activeingredient.

In still another preferred embodiment, the content of the EVA polymer is40±35 wt.-%, more preferably 40±30 wt.-%, still more preferably 40±25wt.-%, yet more preferably 40±20 wt.-%, even more preferably 40±15wt.-%, most preferably 40±10 wt.-% and in particular 40±5 wt.-%,relative to the total weight of the pharmaceutical dosage form or, whenthe pharmaceutical dosage form is multiparticulate, relative to thetotal weight of the particles that contain the pharmacologically activeingredient.

In yet another preferred embodiment, the content of the EVA polymer is50±45 wt.-%, more preferably 50±35 wt.-%, still more preferably 50±25wt.-%, yet more preferably 50±20 wt.-%, even more preferably 50±15wt.-%, most preferably 50±10 wt.-% and in particular 50±5 wt.-%,relative to the total weight of the pharmaceutical dosage form or, whenthe pharmaceutical dosage form is multiparticulate, relative to thetotal weight of the particles that contain the pharmacologically activeingredient.

In even another preferred embodiment, the content of the EVA polymer is55±40 wt.-%, more preferably 55±35 wt.-%, still more preferably 55±25wt.-%, yet more preferably 55±20 wt.-%, even more preferably 55±15wt.-%, most preferably 55±10 wt.-% and in particular 55±5 wt.-%,relative to the total weight of the pharmaceutical dosage form or, whenthe pharmaceutical dosage form is multiparticulate, relative to thetotal weight of the particles that contain the pharmacologically activeingredient.

In a further preferred embodiment, the content of the EVA polymer is60±35 wt.-%, more preferably 60±30 wt.-%, still more preferably 60±25wt.-%, yet more preferably 60±20 wt.-%, even more preferably 60±15wt.-%, most preferably 60±10 wt.-% and in particular 60±5 wt.-%,relative to the total weight of the pharmaceutical dosage form or, whenthe pharmaceutical dosage form is multiparticulate, relative to thetotal weight of the particles that contain the pharmacologically activeingredient.

In still a further preferred embodiment, the content of the EVA polymeris 65±30 wt.-%, more preferably 65±25 wt.-%, still more preferably 65±20wt.-%, yet more preferably 65±15 wt.-%, even more preferably 65±10wt.-%, most preferably 65±7 wt.-% and in particular 65±5 wt.-%, relativeto the total weight of the pharmaceutical dosage form or, when thepharmaceutical dosage form is multiparticulate, relative to the totalweight of the particles that contain the pharmacologically activeingredient.

In yet a further preferred embodiment, the content of the EVA polymer is70±25 wt.-%, more preferably 70±20 wt.-%, still more preferably 70±17wt.-%, yet more preferably 70±13 wt.-%, even more preferably 70±10wt.-%, most preferably 70±7 wt.-% and in particular 70±5 wt.-%, relativeto the total weight of the pharmaceutical dosage form or, when thepharmaceutical dosage form is multiparticulate, relative to the totalweight of the particles that contain the pharmacologically activeingredient.

In even a further preferred embodiment, the content of the EVA polymeris 80±15 wt.-%, more preferably 80±12 wt.-%, still more preferably 80±10wt.-%, yet more preferably 80±8 wt.-%, even more preferably 80±6 wt.-%,most preferably 80±4 wt.-% and in particular 80±2 wt.-%, relative to thetotal weight of the pharmaceutical dosage form or, when thepharmaceutical dosage form is multiparticulate, relative to the totalweight of the particles that contain the pharmacologically activeingredient.

When the pharmaceutical dosage form comprises a prolonged release matrixcontaining the EVA polymer as prolonged release matrix material, thecontent of the EVA polymer is preferably within the range of from 5 to100 wt.-%, more preferably 20 to 98 wt.-%, still more preferably 35 to96 wt.-%, yet more preferably 45 to 95 wt.-%, even more preferably 55 to94 wt.-%, most preferably 65 to 93 wt.-%, and in particular 75 to 92wt.-%, relative to the total weight of the prolonged release matrix,i.e. total weight of the prolonged release matrix material and theoptionally present additional prolonged release matrix material.

Preferably, the relative weight ratio of the EVA polymer to thepharmacologically active ingredient is within the range of 20:1 to 1:20,more preferably 15:1 to 1:15, still more preferably 10:1 to 1:10, yetmore preferably 7:1 to 1:7, most preferably 5:1 to 1:5, and inparticular 3:1 to 1:1.

In a preferred embodiment, when the pharmaceutical dosage form accordingto the invention comprises a prolonged release matrix, the prolongedrelease matrix in turn comprises an additional prolonged release matrixmaterial besides the prolonged release matrix material, i.e. the EVApolymer. Thus, the additional prolonged release matrix material is to bedistinguished from the prolonged release matrix material of theprolonged release matrix of the pharmaceutical dosage form according tothe invention.

Preferably, the additional prolonged release matrix material is apolymer selected from the group comprising polyalkylene oxides, acrylicpolymers, crosslinked acrylic polymers, mixtures of polyvinylpyrrolidone and polyvinyl acetate, waxy materials, polyalkylene glycolsand natural polysaccharides, such as celluloses, cellulose derivativesand xanthan gum.

The content of the additional prolonged release matrix material ispreferably within the range of from 1 to 90 wt.-%, more preferably 2 to80 wt.-%, still more preferably 3 to 70 wt.-%, yet more preferably 3.5to 60 wt.-%, even more preferably 4 to 50 wt.-%, most preferably 4.5 to40 wt.-%, and in particular 5 to 30 wt.-%, relative to the total weightof the prolonged release matrix.

In a preferred embodiment, the content of the additional prolongedrelease matrix material is at least 2 wt.-%, more preferably at least 5wt.-%, still more preferably at least 10 wt.-%, yet more preferably atleast 15 wt.-% and in particular at least 20 wt.-%, either based on thetotal weight of the pharmaceutical dosage form or, when thepharmaceutical dosage form is multiparticulate, based on the totalweight of the particles that contain the pharmacologically activeingredient.

The overall content of additional prolonged release matrix material ispreferably within the range of from 1 to 60 wt.-%, more preferably 2 to45 wt.-%, still more preferably 3 to 35 wt.-%, yet more preferably 4 to28 wt.-%, even more preferably 5 to 25 wt.-%, most preferably 5 to 22wt.-%, and in particular 5 to 20 wt.-%, either based on the total weightof the pharmaceutical dosage form or, when the pharmaceutical dosageform is multiparticulate, based on the total weight of the particlesthat contain the pharmacologically active ingredient.

In a preferred embodiment, the overall content of additional prolongedrelease matrix material is within the range of 5±4 wt.-%, morepreferably 5±3 wt.-%, most preferably 5±2 wt.-%, and in particular 5±1wt.-%, either based on the total weight of the pharmaceutical dosageform or, when the pharmaceutical dosage form is multiparticulate, basedon the total weight of the particles that contain the pharmacologicallyactive ingredient.

In another preferred embodiment, the overall content of additionalprolonged release matrix material is within the range of 7.5±6 wt.-%,more preferably 7.5±4 wt.-%, most preferably 7.5±3 wt.-%, and inparticular 7.5±2 wt.-%, either based on the total weight of thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, based on the total weight of the particles thatcontain the pharmacologically active ingredient.

In still another preferred embodiment, the overall content of additionalprolonged release matrix material is within the range of 10±8 wt.-%,more preferably 10±6 wt.-%, most preferably 10±4 wt.-%, and inparticular 10±2 wt.-%, either based on the total weight of thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, based on the total weight of the particles thatcontain the pharmacologically active ingredient. In yet anotherpreferred embodiment, the overall content of additional prolongedrelease matrix material is within the range of 15±12 wt.-%, morepreferably 15±10 wt.-%, most preferably 15±7 wt.-%, and in particular15±3 wt.-%, either based on the total weight of the pharmaceuticaldosage form or, when the pharmaceutical dosage form is multiparticulate,based on the total weight of the particles that contain thepharmacologically active ingredient.

In even another preferred embodiment, the overall content of additionalprolonged release matrix material is within the range of 20±16 wt.-%,more preferably 20±12 wt.-%, most preferably 20±8 wt.-%, and inparticular 20±4 wt.-%, either based on the total weight of thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, based on the total weight of the particles thatcontain the pharmacologically active ingredient.

In a further preferred embodiment, the overall content of additionalprolonged release matrix material is within the range of 25±20 wt.-%,more preferably 25±15 wt.-%, most preferably 25±10 wt.-%, and inparticular 25±5 wt.-%, either based on the total weight of thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, based on the total weight of the particles thatcontain the pharmacologically active ingredient.

In still a further preferred embodiment, the overall content ofadditional prolonged release matrix material is within the range of30±20 wt.-%, more preferably 30±15 wt.-%, most preferably 30±10 wt.-%,and in particular 30±5 wt.-%, either based on the total weight of thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, based on the total weight of the particles thatcontain the pharmacologically active ingredient.

In yet a further preferred embodiment, the overall content of additionalprolonged release matrix material is within the range of 35±20 wt.-%,more preferably 35±15 wt.-%, most preferably 35±10 wt.-%, and inparticular 35±5 wt.-%, either based on the total weight of thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, based on the total weight of the particles thatcontain the pharmacologically active ingredient.

In even a further preferred embodiment, the overall content ofadditional prolonged release matrix material is within the range of40±20 wt.-%, more preferably 40±15 wt.-%, and most preferably 40±10wt.-%, and in particular 40±5 wt.-%, either based on the total weight ofthe pharmaceutical dosage form or, when the pharmaceutical dosage formis multiparticulate, based on the total weight of the particles thatcontain the pharmacologically active ingredient.

In another preferred embodiment, the overall content of additionalprolonged release matrix material is within the range of 45±20 wt.-%,more preferably 45±15 wt.-%, and most preferably 45±10 wt.-%, and inparticular 45±5 wt.-%, either based on the total weight of thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, based on the total weight of the particles thatcontain the pharmacologically active ingredient.

In still another preferred embodiment, the overall content of additionalprolonged release matrix material is within the range of 50±20 wt.-%,more preferably 50±15 wt.-%, and most preferably 50±10 wt.-%, and inparticular 50±5 wt.-%, either based on the total weight of thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, based on the total weight of the particles thatcontain the pharmacologically active ingredient.

Preferably, the relative weight ratio of the additional prolongedrelease matrix material to the pharmacologically active ingredient iswithin the range of 20:1 to 1:20, more preferably 10:1 to 1:15, stillmore preferably 7:1 to 1:10, yet more preferably 5:1 to 1:7, mostpreferably 1:1 to 1:5, and in particular 1:2 to 1:5.

Preferably, the relative weight ratio of the additional prolongedrelease matrix material to the prolonged release matrix material of theprolonged release matrix is within the range of 20:1 to 1:20, morepreferably 10:1 to 1:18, still more preferably 7:1 to 1:16, yet morepreferably 5:1 to 1:14, most preferably 1:1 to 1:12, and in particular1:5 to 1:10.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention comprises a prolonged release matrix which in turncomprises

-   (i) an EVA polymer as a prolonged release matrix material, wherein    the EVA polymer comprises a single EVA polymer having a melt flow    rate at 190° C. and 2.16 kg of 52±2 g/10 min measured according to    ASTM D1238 and preferably containing 60±5 wt.-% of ethylene    repetition units, relative to the total weight of the EVA polymer;    and-   (ii) an additional prolonged release matrix material which is    preferably a polymer selected from the group consisting of    polyalkylene oxides, crosslinked acrylic polymers and matrices based    on polyvinyl acetate and polyvinyl pyrrolidone;    wherein-   (iii) the relative weight content of the prolonged release matrix    material is preferably greater than the relative weight content of    the additional prolonged release matrix material.

In a preferred embodiment, the additional prolonged release matrixmaterial is a polyalkylene oxide, preferably a polyethylene oxide,particularly preferably having a weight average molecular weight of atleast 500,000 g/mol.

When the additional prolonged release matrix material of the prolongedrelease matrix comprises a polyalkylene oxide, it preferably does notadditionally comprise any other additional prolonged release matrixmaterial.

When the pharmaceutical dosage form or, when the pharmaceutical dosageform is multiparticulate, the particles is/are film coated, thepolyalkylene oxide is preferably homogeneously distributed within thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, the particles, i.e. the film coating preferably doesnot contain polyalkylene oxide. Nonetheless, the film coating as suchmay of course contain one or more polymers, which however, preferablydiffer from the polyalkylene oxide contained in the pharmaceuticaldosage form or, when the pharmaceutical dosage form is multiparticulate,the particles.

Preferably, the polyalkylene oxide is selected from polymethylene oxide,polyethylene oxide and polypropylene oxide, or copolymers or mixturesthereof.

Preferably, the polyalkylene oxide has a weight average molecular weight(M_(W)), preferably also a viscosity average molecular weight (M_(η)) ofmore than 200,000 g/mol or at least 500,000 g/mol, preferably at least1,000,000 g/mol or at least 2,500,000 g/mol, more preferably in therange of about 1,000,000 g/mol to about 15,000,000 g/mol, and mostpreferably in the range of about 5,000,000 g/mol to about 10,000,000g/mol. Suitable methods to determine M_(W) and M_(η) are known to aperson skilled in the art. M_(η) is preferably determined by rheologicalmeasurements, whereas M_(W) can be determined by gel permeationchromatography (GPC).

Preferably, the molecular weight dispersity M_(W)/M_(η) of thepolyalkylene oxide is within the range of 2.5±2.0, more preferably2.5±1.5, still more preferably 2.5±1.0, yet more preferably 2.5±0.8,most preferably 2.5±0.6, and in particular 2.5±0.4.

The polyalkylene oxide preferably has a viscosity at 25° C. of 30 to17,600 mPa·s, more preferably 55 to 17,600 mPa·s, still more preferably600 to 17,600 mPa·s, yet more preferably 4,500 to 17,600 mPa·s, evenmore preferably 4,500 to 12,000 mPa·s, most preferably 5,000 to 10,500mPa·s and in particular 5,500 to 7,500 mPa·s or 7,500 to 10,000 mPa·s,measured in a 1 wt.-% aqueous solution.

The polyalkylene oxide may comprise a single polyalkylene oxide having aparticular average molecular weight, or a mixture (blend) of differentpolymers, such as two, three, four or five polymers, e.g., polymers ofthe same chemical nature but different average molecular weight,polymers of different chemical nature but same average molecular weight,or polymers of different chemical nature as well as different molecularweight.

For the purpose of specification, a polyalkylene glycol has a molecularweight of up to 20,000 g/mol whereas a polyalkylene oxide has amolecular weight of more than 20,000 g/mol. Preferably, the weightaverage over all molecular weights of all polyalkylene oxides that arecontained in the pharmaceutical dosage form is more than 200,000 g/mol.Thus, polyalkylene glycols, if any, are preferably not taken intoconsideration when determining the weight average molecular weight ofpolyalkylene oxide.

In a particularly preferred embodiment, the additional prolonged releasematrix material is a polyalkylene oxide, more preferably a polyethyleneoxide, having a weight average molecular weight (M_(W)), preferably alsoa viscosity average molecular weight (M_(η)) in the range of about5,000,000 g/mol to about 10,000,000 g/mol.

The overall content of polyalkylene oxide is preferably within the rangeof from 1 to 60 wt.-%, more preferably 3 to 45 wt.-%, still morepreferably 5 to 35 wt.-%, yet more preferably 7 to 28 wt.-%, even morepreferably 8 to 25 wt.-%, most preferably 9 to 22 wt.-%, and inparticular 10 to 20 wt.-%, either based on the total weight of thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, based on the total weight of the particles thatcontain the pharmacologically active ingredient.

In a preferred embodiment, the overall content of polyalkylene oxide iswithin the range of 15±12 wt.-%, more preferably 15±10 wt.-%, mostpreferably 15±7 wt.-%, and in particular 15±3 wt.-%, either based on thetotal weight of the pharmaceutical dosage form or, when thepharmaceutical dosage form is multiparticulate, based on the totalweight of the particles that contain the pharmacologically activeingredient.

In a preferred embodiment, the additional prolonged release matrixmaterial is a mixture of polyvinyl pyrrolidone and polyvinyl acetate.

When the additional prolonged release matrix material of the prolongedrelease matrix comprises a mixture of polyvinyl pyrrolidone andpolyvinyl acetate, it preferably does not additionally comprise anyother additional prolonged release matrix material.

When the pharmaceutical dosage form or, when the pharmaceutical dosageform is multiparticulate, the particles is/are film coated, the mixtureof polyvinyl pyrrolidone and polyvinyl acetate is preferablyhomogeneously distributed within the pharmaceutical dosage form or, whenthe pharmaceutical dosage form is multiparticulate, the particles, i.e.the film coating preferably does not contain any mixture of polyvinylpyrrolidone and polyvinyl acetate. Nonetheless, the film coating as suchmay of course contain one or more polymers, which however, preferablydiffer from the mixture of polyvinyl pyrrolidone and polyvinyl acetatecontained in the pharmaceutical dosage form or, when the pharmaceuticaldosage form is multiparticulate, the particles.

Preferably, the mixture of polyvinyl pyrrolidone and polyvinyl acetatecontains 10 to 30 wt.-% polyvinyl pyrrolidone and 70 to 90 wt.-% ofpolyvinyl acetate, more preferably 18 to 21 wt.-% polyvinyl pyrrolidoneand 75 to 85 wt.-% of polyvinyl acetate and most preferably 19 wt.-%polyvinyl pyrrolidone and 80 wt.-% of polyvinyl acetate.

The weight ratio between polyvinyl acetate and polyvinyl pyrrolidonepreferably is in the range from 20:1 to 1:20, more preferably 16:1 to1:10, still more preferably 13:1 to 1:5, yet more preferably 10:1 to1:2, even more preferably 7:1 to 1:1, most preferably 5:1 to 2:1 and inparticular 4.5:1 to 3.5:1.

Preferably, the polyvinyl acetate has a weight average molecular weight(M_(W)) of 450,000±100,000 g/mol, more preferably 450,000±80,000 g/mol,still more preferably 450,000±50,000 g/mol, yet more preferably450,000±10,000 g/mol, even more preferably 450,000±1,000 g/mol, mostpreferably 450,000±500 g/mol and in particular 450,000±100 g/mol. M_(W)can be determined by gel permeation chromatography (GPC).

Preferably, the polyvinyl pyrrolidone has a weight average molecularweight (M_(W)) of 50,000±10,000 g/mol, more preferably 50,000±8,000g/mol, still more preferably 50,000±5,000 g/mol, yet more preferably50,000±1,000 g/mol, even more preferably 50,000±800 g/mol, mostpreferably 50,000±500 g/mol and in particular 50,000±100 g/mol.

The weight average molecular weight (M_(W)) of the mixture of polyvinylpyrrolidone and polyvinyl acetate can be expressed as K-value accordingto the method described in the USP and Ph. Eur. monographs “Povidone”,measured in a 1% solution in tetrahydrofurane, wherein the K-valuepreferably is in the range of from 40 to 80, more preferably 45 to 78,still more preferably 50 to 75, most preferably 55 to 70 and inparticular 60 to 65.

Preferably, the glass transition temperature (T_(g)) of the mixture ofpolyvinyl pyrrolidone and polyvinyl acetate is in the range of 35±10°C., more preferably 35±6° C. and most preferably 35±3° C.

In a particularly preferred embodiment, the additional prolonged releasematrix material is a mixture of polyvinyl pyrrolidone and polyvinylacetate, wherein said mixture has a K-value in the range of from 60 to65, measured in a 1% solution in tetrahydrofurane according to themethod described in the USP and Ph. Eur. monographs “Povidone” and/orwherein the weight ratio between polyvinyl acetate and polyvinylpyrrolidone is in the range of 4.5:1 to 3.5:1.

The overall content of the mixture of polyvinyl pyrrolidone andpolyvinyl acetate is preferably within the range of from 1.0 to 60wt.-%, more preferably 2.0 to 50 wt.-%, still more preferably 3.0 to 40wt.-%, yet more preferably 3.5 to 30 wt.-%, even more preferably 4.0 to25 wt.-%, most preferably 4.5 to 20 wt.-%, and in particular 5 to 15wt.-%, either based on the total weight of the pharmaceutical dosageform or, when the pharmaceutical dosage form is multiparticulate, basedon the total weight of the particles that contain the pharmacologicallyactive ingredient.

In a preferred embodiment, the overall content of the mixture ofpolyvinyl pyrrolidone and polyvinyl acetate is within the range of 10±8wt.-%, more preferably 10±6 wt.-%, most preferably 10±4 wt.-%, and inparticular 10±2 wt.-%, either based on the total weight of thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, based on the total weight of the particles thatcontain the pharmacologically active ingredient.

Mixtures of polyvinyl pyrrolidone and polyvinyl acetate that aresuitable for use in the pharmaceutical dosage forms according to theinvention are commercially available, e.g. from BASF, such as Kollidon®SR. For details concerning the properties of this product, it can bereferred to e.g. the product specification.

In another preferred embodiment, the additional prolonged release matrixmaterial is an acrylic polymer.

When the additional prolonged release matrix material of the prolongedrelease matrix comprises an acrylic polymer, it preferably does notadditionally comprise any other additional prolonged release matrixmaterial.

When the pharmaceutical dosage form or, when the pharmaceutical dosageform is multiparticulate, the particles is/are film coated, the acrylicpolymer is preferably homogeneously distributed within thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, the particles, i.e. the film coating preferably doesnot contain acrylic polymer. Nonetheless, the film coating as such mayof course contain one or more polymers, which however, preferably differfrom the acrylic polymer contained in the pharmaceutical dosage form or,when the pharmaceutical dosage form is multiparticulate, the particles.

Preferably, the acrylic polymer has a weight average molecular weightwithin the range of from 100,000 g/mol to 2,000,000 g/mol. In apreferred embodiment, the acrylic polymer has a weight average molecularweight (M_(W)) or viscosity average molecular weight (M_(η)) of at least150,000 or at least 200,000 g/mol, preferably at least 250,000 g/mol orat least 300,000 g/mol, more preferably in the range of about 300,000g/mol to about 2,000,000 g/mol, and most preferably in the range ofabout 300,000 g/mol to about 1,000,000 g/mol. Suitable methods todetermine M_(W) and M_(η) are known to a person skilled in the art.M_(η) is preferably determined by rheological measurements, whereasM_(W) can be determined by gel permeation chromatography (GPC).

The acrylic polymer can be a nonionic acrylic polymer or an ionicacrylic polymer. For the purpose of specification, “nonionic polymer”refers to a polymer not containing more than 1 mole.-% ionic, i.e.anionic or cationic, monomer units, preferably containing no ionicmonomer units at all.

In a preferred embodiment, the additional prolonged release matrixmaterial is an ionic acrylic polymer.

Preferred ionic acrylic polymers are anionic acrylic polymers. Preferredanionic acrylic polymers include but are not limited to homopolymers orcopolymers of one or two different C₁₋₄-alkyl(meth)acrylate monomers andcopolymerizable anionic monomers such as acrylic acid.

For the purpose of the specification, “(meth)acryl” refers to acryl aswell as methacryl.

In a preferred embodiment, the additional prolonged release matrixmaterial is an anionic acrylic polymer, preferably polyacrylic acid.According to this embodiment, the polyacrylic acid preferably has aviscosity within the range of 2,000 to 20,000 mPa·s, more preferably3,000 to 18,000 mPa·s, still more preferably 3,500 to 16,000 mPa·s, yetmore preferably 3,600 to 14,000 mPa·s, even more preferably 3,700 to13,000 mPa·s, most preferably 3,800 to 12,000, and in particular 4,000to 11,000 mPa·s, measured with a Brookfield RVT, 20 rpm, spindle no. 5at 25° C. and 0.5 wt.-% neutralized to pH 7.3-7.8.

The acrylic polymer, preferably the anionic acrylic polymer, morepreferably the polyacrylic acid polymer can optionally be crosslinked.Preferred crosslinking agents include allyl pentaerythritol, allylsucrose, ethylene glycol di(methacrylate), methylenebisacrylamide anddivinyl benzene.

In a particularly preferred embodiment, the anionic acrylic polymer is apolyacrylic acid polymer which is crosslinked, preferably with allypentaerythritol, and has a viscosity of 4,000 to 11,000 mPa·s, measuredwith a Brookfield RVT, 20 rpm, spindle no. 5 at 25° C. and 0.5 wt.-%neutralized to pH 7.3-7.8.

Preferably, the overall content of anionic acrylic polymer, preferablypolyacrylic acid, more preferably crosslinked polyacrylic acid, iswithin the range of from 1.0 to 60 wt.-%, more preferably 2.0 to 50wt.-%, still more preferably 3.0 to 40 wt.-%, yet more preferably 3.5 to30 wt.-%, even more preferably 4.0 to 20 wt.-%, most preferably 4.5 to15 wt.-%, and in particular 5.0 to 12 wt.-%, either based on the totalweight of the pharmaceutical dosage form or, when the pharmaceuticaldosage form is multiparticulate, based on the total weight of theparticles that contain the pharmacologically active ingredient.

Polyacrylic acid polymers that are suitable for use in thepharmaceutical dosage forms according to the invention are commerciallyavailable, e.g. from Lubrizol, such as Carbopol® 71G, Carbopol® 971P,Carbopol® 981 and Carbopol® 941. For details concerning the propertiesof these products, it can be referred to e.g. the product specification.

Other preferred anionic acrylic polymers are ternary copolymers ofmethyl acrylate, methyl methacrylate and methacrylic acid. Preferably,the anionic acrylic polymer has a weight average molecular weight withinthe range of 280,000±250,000 g/mol, more preferably 280,000±200,000g/mol, still more preferably 280,000±180,000 g/mol, yet more preferably280,000±160,000 g/mol, even more preferably 280,000±140,000 g/mol, mostpreferably 280,000±120,000 g/mol, and in particular 280,000±100,000g/mol.

Further preferred ionic acrylic polymers are cationic acrylic polymers.Preferred cationic acrylic polymers include but are not limited tocopolymers of one or two different C₁₋₄-alkyl(meth)acrylate monomers andcopolymerizable cationic monomers such as trimethylammonioethylmethacrylate chloride. Preferred representatives are ternary copolymersof ethyl acrylate, methyl methacrylate and a low content of methacrylicacid ester with quaternary ammonium groups, preferablytrimethylammonioethyl methacrylate chloride. Preferably, the cationicacrylic polymer has a weight average molecular weight within the rangeof 32,000±30,000 g/mol, more preferably 32,000±27,000 g/mol, still morepreferably 32,000±23,000 g/mol, yet more preferably 32,000±20,000 g/mol,even more preferably 32,000±17,000 g/mol, most preferably 32,000±13,000g/mol, and in particular 32,000±10,000 g/mol.

In another preferred embodiment, the additional prolonged release matrixmaterial is a nonionic acrylic polymer.

Nonionic acrylic polymers that are suitable for use in thepharmaceutical dosage forms according to the invention are commerciallyavailable, e.g. from Evonik. For example, Eudragit® NE30D, Eudragit®NE40D and Eudragit® NM30D, which are provided as aqueous dispersions ofpoly(ethyl acrylate-co-methyl methacrylate) 2:1, may be used in thepharmaceutical dosage form according to the invention. For detailsconcerning the properties of these products, it can be referred to e.g.the product specification.

In another preferred embodiment, the additional prolonged release matrixmaterial is a waxy material.

Preferably, the waxy material is selected from the group consisting of

-   -   glycerides, especially monoglycerides, diglycerides,        triglycerides,    -   esters of fatty acids with fatty alcohols, and    -   paraffins.

When the additional prolonged release matrix material of the prolongedrelease matrix comprises a waxy material, it preferably does notadditionally comprise any other additional prolonged release matrixmaterial.

As used herein a “waxy material” refers to a material which melts intoliquid form having low viscosity upon heating and sets again to a solidstate upon cooling. Preferably, the waxy material has a melting point ofat least 30° C., more preferably at least 35° C., still more preferablyat least 40° C., yet more preferably at least 45° C., even morepreferably at least 50° C., most preferably at least 55° C., and inparticular at least 60° C.

When the waxy material is or comprises a monoglyceride, diglyceride,triglyceride or a mixture thereof, it is preferably a mono-, di- ortriester of glycerol and carboxylic acids, whereas the carboxylic acidis preferably selected from the group consisting of fatty acids, hydroxyfatty acids and aromatic acids.

Preferred glycerides of fatty acids include monoglycerides,diglycerides, triglycerides, and mixtures thereof; preferably of C₆ toC₂₂ fatty acids. Especially preferred are partial glycerides of the C₁₆to C₂₂ fatty acids such as glycerol behenat, glycerol palmitostearate,glycerol monostearate, glycerol trimyristate and glycerol distearate.

The term “fatty acid” is well acknowledged in the art and includes forexample unsaturated representatives such as myristoleic acid,palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenicacid, linoleic acid, linoelaidic acid, α-linolenic acid, arachidonicacid, eicosapentaenoic acid, erucic acid, and docosahexaenoic acid; aswell as saturated representatives such as caprylic acid, capric acid,lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid,behenic acid, lignoceric acid, and cerotic acid.

The term “hydroxy fatty acid” is also well acknowledged in the art andincludes for example 2-hydroxyhexanoic acid, 2-hydroxyoctanoic acid,2-hydroxydecanoic acid, 2-hydroxy-dodecanoic acid, β-hydroxylauric acid,2-hydroxytetradecanoic acid, β-hydroxymyristic acid,15-hydroxypentadecanoic acid, 16-hydroxyhexadecanoic acid,β-hydroxypalmitic acid, 12-hydroxyoctadecanoic acid, α-hydroxystearicacid, and α-hydroxyarachidic acid.

The fatty acids and the hydroxy fatty acids are preferably saturated.

When the waxy material is or comprises a diglyceride or a triglyceride,the fatty acids, hydroxy fatty acids and aromatic acids, respectively,may be identical or different.

According to this embodiment of the invention, the waxy material ispreferably a hard fat (adeps solidus) in accordance with Ph. Eur.

Preferably, the waxy material is a monoglyceride, diglyceride,triglyceride or a mixture thereof, selected from the group consisting ofhydrogenated soybean oil, hydrogenated palm oil, hydrogenated castoroil, hydrogenated cottonseed oil, and mixtures thereof.

When the waxy material is or comprises an ester of a fatty acid with afatty alcohol, the fatty acid is preferably a saturated fatty acid.Preferred examples of fatty acids are already mentioned above inconnection with the glycerides. The fatty alcohol is preferably derivedfrom a fatty acid and preferably also saturated.

Preferred representatives of esters of fatty acids with fatty alcoholsinclude but are not limited to natural waxes such as beeswax,carnaubawax, cetyl palmitate, oleyl oleate, spermaceti (cetaceum),candelilla wax, ouricury wax, sugarcane wax, and retamo wax.

When the waxy material is or comprises a paraffin, the paraffin ispreferably a hard paraffin (paraffinum solidum, ceresin, zeresin) inaccordance with Ph. Eur.

The waxy material may comprise a single waxy material, or a mixture(blend) of different waxy materials, such as two, three, four or fivewaxy materials, each of which preferably being selected from the groupconsisting of glycerides, especially monoglycerides, diglycerides,triglycerides; esters of fatty acids with fatty alcohols; and paraffins.

Waxy materials that are suitable for use in the pharmaceutical dosageforms according to the invention are commercially available, e.g. Ceraalba, Cera flava, Kolliwax™ HCO, Dynasan® 118, Compritol® 888 ATO,Precirol® ATO 5, Gelucire® 44/14. For details concerning the propertiesof these products, it can be referred to e.g. the product specification.

Preferred polyalkylene glycols include but are not limited topolymethylene oxide, polyethylene oxide, polypropylene oxide, and thecopolymers and mixtures thereof. For the purpose of the specification, apolyalkylene glycol has a molecular weight of up to 20,000 g/mol whereasa polyalkylene oxide has a molecular weight of more than 20,000 g/mol.

In a preferred embodiment, the polyalkylene glycol has a weight averagemolecular weight (M_(W)) or viscosity average molecular weight (M_(η))in the range of about 1,000 g/mol to about 18000 g/mol, and mostpreferably in the range of about 5,000 g/mol to about 8,000 g/mol.Suitable methods to determine M_(W) and M_(η) are known to a personskilled in the art. M_(η) is preferably determined by rheologicalmeasurements, whereas M_(W) can be determined by gel permeationchromatography (GPC).

Preferred celluloses and cellulose derivatives include but are notlimited to microcrystalline cellulose, cellulose esters and celluloseethers.

Preferred cellulose ethers include nonionic cellulose ethers such asmethylcellulose, ethylcellulose, propylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,and hydroxypropylmethylcellulose; as well as ionic cellulose ethers,i.e. cationic cellulose ethers or anionic cellulose ethers such ascarboxymethyl cellulose.

In view of their good solubility in aqueous ethanol, however,ethylcellulose and propylcellulose are preferably only contained incomparatively low amounts (preferably at most 1.0 wt.-%) or notcontained at all in the pharmaceutical dosage form according to theinvention.

Preferred xanthan gums include but are not limited to Grindsted® Xanthan80 Pharma available from Danisco and CEROGA Xanthan Gum Type 602available from Roeper.

Suitable xanthan gums which are commercially available include XANTURAL®75, XANTURAL® 180 and XANTURAL® 11K from CP Kelco; VANZAN® NF, VANZAN®NF-F, VANZAN® NF-C from Vanderbilt Minerals; Haixan® PM80, Haixan®PM200, Haixan® PM40 from Zibo Hailan Chemical Co.; Xanthan GumPharmaceutical Grade PHARM200 from ICD Biochemistry Co. and Xanthan Gumfrom Jungbunzlauer.

Alternatively or additionally, the additional prolonged release matrixmaterial may comprise one or more polymers, preferably selected from thegroup consisting of polyethylene, polypropylene, polyvinyl chloride,polycarbonate, polystyrene, polyvinylpyrrolidone, poly(alk)acrylate,poly(hydroxy fatty acids), such as for examplepoly(3-hydroxybutyrate-co-3-hydroxyvalerate) (Biopol®),poly(hydroxyvaleric acid), polycaprolactone, polyvinyl alcohol,polyesteramide, polyethylene succinate, polylactone, polyglycolide,polyurethane, polyamide, polylactide, polyacetal (for examplepolysaccharides optionally with modified side chains),polylactide/glycolide, polylactone, polyglycolide, polyorthoester,polyanhydride, block polymers of polyethylene glycol and polybutyleneterephthalate (Polyactive®), polyanhydride (Polifeprosan), copolymersthereof, block-copolymers thereof (e.g., Poloxamer®), and mixtures of atleast two of the stated polymers, or other polymers with the abovecharacteristics.

The pharmaceutical dosage form or, when it is multiparticulate, theparticles according to the invention which contain the pharmacologicallyactive ingredient may contain additional pharmaceutical excipientsconventionally contained in pharmaceutical dosage forms in conventionalamounts, such as antioxidants, preservatives, lubricants, plasticizer,fillers, binders, and the like.

The skilled person will readily be able to determine appropriate furtherexcipients as well as the quantities of each of these excipients.Specific examples of pharmaceutically acceptable carriers and excipientsare described in the Handbook of Pharmaceutical Excipients, AmericanPharmaceutical Association (1986).

In a preferred embodiment, the pharmaceutical dosage form or, when it ismultiparticulate, the particles according to the invention which containthe pharmacologically active ingredient do not contain a disintegrant.According to this embodiment, the pharmaceutical dosage form or, when itis multiparticulate, the particles according to the invention whichcontain the pharmacologically active ingredient preferably do notcontain sodium starch glycolate.

Preferably, the pharmaceutical dosage form or, when it ismultiparticulate, the particles according to the invention which containthe pharmacologically active ingredient further comprise an antioxidant.Suitable antioxidants include ascorbic acid, butylated hydroxyanisole(BHA), butylated hydroxytoluene (BHT), salts of ascorbic acid,monothioglycerol, phosphorous acid, vitamin C, vitamin E and thederivatives thereof, coniferyl benzoate, nordihydroguajaretic acid,gallus acid esters, sodium bisulfite, particularly preferablybutylhydroxytoluene or butylhydroxyanisole and α-tocopherol. Theantioxidant is preferably present in quantities of 0.01 wt.-% to 10wt.-%, more preferably of 0.03 wt.-% to 5 wt.-%, most preferably of 0.05wt.-% to 2.5 wt.-%, based on the total weight of the pharmaceuticaldosage form and the particles, respectively.

In a preferred embodiment, the pharmaceutical dosage form or, when it ismultiparticulate, the particles according to the invention which containthe pharmacologically active ingredient further comprise an acid,preferably citric acid. The amount of acid is preferably in the range of0.01 wt.-% to about 20 wt.-%, more preferably in the range of 0.02 wt.-%to about 10 wt.-%, and still more preferably in the range of 0.05 wt.-%to about 5 wt.-%, and most preferably in the range of 0.1 wt.-% to about1.0 wt.-%, based on the total weight of the pharmaceutical dosage formand the particles, respectively.

In a preferred embodiment, the pharmaceutical dosage form or, when it ismultiparticulate, the particles according to the invention which containthe pharmacologically active ingredient contain at least one lubricant.In another preferred embodiment, the pharmaceutical dosage form or, whenit is multiparticulate, the particles according to the invention whichcontain the pharmacologically active ingredient contain no lubricant.

Especially preferred lubricants are selected from

-   -   magnesium stearate and stearic acid;    -   polyoxyethylene glycerol fatty acid esters, such as mixtures of        mono-, di- and triesters of glycerol and di- and monoesters of        macrogols having molecular weights within the range of from 200        to 4000 g/mol, e.g., macrogolglycerolcaprylocaprate,        macrogolglycerollaurate, macrogolglycerolococoate,        macrogolglycerollinoleate, macrogol-20-glycerolmonostearate,        macrogol-6-glycerolcaprylocaprate, macrogolglycerololeate;        macrogolglycerolstearate, macrogolglycerolhydroxystearate, and        macrogolglycerolrizinoleate;    -   polyglycolyzed glycerides, such as the one known and        commercially available under the trade name “Labrasol”;    -   fatty alcohols that may be linear or branched, such as        cetylalcohol, stearylalcohol, cetylstearyl alcohol,        2-octyldodecane-1-ol and 2-hexyldecane-1-ol; and    -   polyethylene glycols having a molecular weight between 10.000        and 60.000 g/mol.

Preferably, the amount of the lubricant ranges from 0.01 wt.-% to about10 wt.-%, more preferably in the range of 0.05 wt.-% to about 7.5 wt.-%,most preferably in the range of 0.1 wt.-% to about 5 wt.-%, and inparticular in the range of 0.1 wt.-% to about 1 wt.-%, based on thetotal weight of the pharmaceutical dosage form and the particles,respectively.

Preferably, the pharmaceutical dosage form or, when it ismultiparticulate, the particles according to the invention which containthe pharmacologically active ingredient further comprise a plasticizer.The plasticizer improves the processability of the prolonged releasematrix material and additional prolonged release matrix material,respectively. A preferred plasticizer is polyalkylene glycol, likepolyethylene glycol, triacetin, fatty acids, fatty acid esters, waxesand/or microcrystalline waxes. Particularly preferred plasticizers arepolyethylene glycols, such as PEG 6000.

Preferably, the content of the plasticizer is within the range of from0.5 to 30 wt.-%, more preferably 1.0 to 25 wt.-%, still more preferably2.5 wt.-% to 22.5 wt.-%, yet more preferably 5.0 wt.-% to 20 wt.-%, mostpreferably 6 to 20 wt.-% and in particular 7 wt.-% to 17.5 wt.-%, basedon the total weight of the pharmaceutical dosage form and the particles,respectively.

Plasticizers can sometimes act as a lubricant, and lubricants cansometimes act as a plasticizer.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention contains no substances which irritate the nasal passagesand/or pharynx, i.e. substances which, when administered via the nasalpassages and/or pharynx, bring about a physical reaction which is eitherso unpleasant for the patient that he/she does not wish to or cannotcontinue administration, for example burning, or physiologicallycounteracts taking of the corresponding active compound, for example dueto increased nasal secretion or sneezing. Further examples of substanceswhich irritate the nasal passages and/or pharynx are those which causeburning, itching, urge to sneeze, increased formation of secretions or acombination of at least two of these stimuli. Corresponding substancesand the quantities thereof which are conventionally to be used are knownto the person skilled in the art. Some of the substances which irritatethe nasal passages and/or pharynx are accordingly based on one or moreconstituents or one or more plant parts of a hot substance drug.Corresponding hot substance drugs are known per se to the person skilledin the art and are described, for example, in “PharmazeutischeBiologie—Drogen and ihre Inhaltsstoffe” by Prof. Dr. Hildebert Wagner,2nd., revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982,pages 82 et seq. The corresponding description is hereby introduced as areference and is deemed to be part of the disclosure.

The pharmaceutical dosage form according to the invention furthermorepreferably contains no antagonists for the pharmacologically activeingredient, preferably no antagonists against psychotropic substances,in particular no antagonists against opioids. Antagonists suitable for agiven pharmacologically active ingredient are known to the personskilled in the art and may be present as such or in the form ofcorresponding derivatives, in particular esters or ethers, or in eachcase in the form of corresponding physiologically acceptable compounds,in particular in the form of the salts or solvates thereof. Thepharmaceutical dosage form according to the invention preferablycontains no antagonists selected from among the group comprisingnaloxone, naltrexone, nalmefene, nalide, nalmexone, nalorphine ornaluphine, in each case optionally in the form of a correspondingphysiologically acceptable compound, in particular in the form of abase, a salt or solvate; and no neuroleptics, for example a compoundselected from among the group comprising haloperidol, promethacine,fluphenazine, perphenazine, levomepromazine, thioridazine, perazine,chlorpromazine, chlorprothixine, zuclopenthixol, flupentixol,prothipendyl, zotepine, benperidol, pipamperone, melperone andbromperidol.

The pharmaceutical dosage form according to the invention furthermorepreferably contains no emetic. Emetics are known to the person skilledin the art and may be present as such or in the form of correspondingderivatives, in particular esters or ethers, or in each case in the formof corresponding physiologically acceptable compounds, in particular inthe form of the salts or solvates thereof. The pharmaceutical dosageform according to the invention preferably contains no emetic based onone or more constituents of ipecacuanha (ipecac) root, for example basedon the constituent emetine, as are, for example, described in“Pharmazeutische Biologie—Drogen and ihre Inhaltsstoffe” by Prof. Dr.Hildebert Wagner, 2nd, revised edition, Gustav Fischer Verlag,Stuttgart, N.Y., 1982. The corresponding literature description ishereby introduced as a reference and is deemed to be part of thedisclosure. The pharmaceutical dosage form according to the inventionpreferably also contains no apomorphine as an emetic.

Finally, the pharmaceutical dosage form according to the inventionpreferably also contains no bitter substance. Bitter substances and thequantities effective for use may be found in US-2003/0064099 A1, thecorresponding disclosure of which should be deemed to be the disclosureof the present application and is hereby introduced as a reference.Examples of bitter substances are aromatic oils, such as peppermint oil,eucalyptus oil, bitter almond oil, menthol, fruit aroma substances,aroma substances from lemons, oranges, limes, grapefruit or mixturesthereof, and/or denatonium benzoate.

The pharmaceutical dosage form according to the invention accordinglypreferably contains neither substances which irritate the nasal passagesand/or pharynx, nor antagonists for the pharmacologically activeingredient, nor emetics, nor bitter substances.

In a preferred embodiment, the pharmaceutical dosage form providesprolonged release of the pharmacologically active ingredient.

Particularly preferably, the pharmacologically active ingredient isembedded in a prolonged release matrix comprising the EVA polymer,wherein the prolonged release matrix provides prolonged release of thepharmacologically active ingredient.

For the purpose of specification “prolonged release” preferably means aproduct in which the rate of release of active compound from theformulation after administration has been reduced over time, in order tomaintain therapeutic activity, to reduce toxic effects, or for someother therapeutic purpose such as reducing the dosing frequency.

Preferably, under physiological conditions the pharmaceutical dosageform according to the invention has released after 30 minutes 0.1 to75%, after 240 minutes 0.5 to 95%, after 480 minutes 1.0 to 100% andafter 720 minutes 2.5 to 100% of the pharmacologically active ingredient(A). Further preferred release profiles R₁ to R₈ are summarized in thetable here below [all data in wt.-% of released pharmacologically activeingredient]:

time R₁ R₂ R₃ R₄ R₅ R₆ R₇ R₈  60 min 0-30 0-50 0-50 15-25 20-30 20-5040-70  40-80  120 min 0-40 0-75 0-75 25-40 35-50 40-75 60-95  80-100 240min 3-55 3-95 10-95  40-70 55-75 60-95 80-100 480 min 10-65  10-10035-100 60-90 80-95  80-100 90-100 720 min 20-75  20-100 55-100  70-100 90-100  90-100 960 min 30-88  30-100 70-100 >80  95-100 1440 min 50-100 50-100 >90 2160 min  >80 >80

Further preferred release profiles R₉ to R₁₆ are summarized in the tablehere below [all data in wt.-% of released pharmacologically activeingredient]:

time R₉ R₁₀ R₁₁ R₁₂ R₁₃ R₁₄ R₁₅ R₁₆  30 min 17.5 ± 7.5 25 ± 15 30 ± 1530 ± 15 12 ± 10 5 ± 4  2 ± 1.5 50 ± 15  60 min 27.0 ± 8.0 35 ± 15 38 ±10 38 ± 10 18 ± 15 6 ± 4 3 ± 2 70 ± 10 120 min 41.5 ± 9.5 43 ± 15 48 ±10 48 ± 10 20 ± 10 8 ± 4 4 ± 2 88 ± 10 240 min  64.5 ± 12.5 60 ± 15 55 ±10 60 ± 10 32 ± 10 9 ± 5 5 ± 3 90 ± 8  480 min  88.0 ± 12.0 83 ± 10 63 ±10 68 ± 10 50 ± 10 10 ± 5  6 ± 4 >95 720 min 96.0 ± 9.0 98 ± 2  67 ± 1070 ± 10 60 ± 10 12 ± 5  6.5 ± 5  840 min 97.5 ± 7.5 >98 70 ± 15 73 ± 1565 ± 20 17 ± 10 7 ± 6

Suitable in vitro conditions are known to the skilled artisan. In thisregard it can be referred to, e.g., the Eur. Ph. Preferably, the releaseprofile is measured under the following conditions: Paddle apparatusequipped without sinker, 50 rpm, 37±5° C., 900 mL simulated intestinalfluid pH 6.8 (phosphate buffer) or pH 4.5. In a preferred embodiment,the rotational speed of the paddle is increased to 75 rpm.

Preferably, the release profile, the pharmacologically activeingredient, the EVA polymer, the optionally present additional prolongedrelease matrix material and the optionally present pharmaceuticalexcipients of the pharmaceutical dosage form according to the inventionare stable upon storage, preferably upon storage at elevatedtemperature, e.g. 40° C., for 3 months in sealed containers.

In connection with the release profile, the term “stable” preferablymeans that when comparing the initial release profile with the releaseprofile after storage, at any given time point the release profilesdeviate from one another by not more than 20%, more preferably not morethan 15%, still more preferably not more than 10%, yet more preferablynot more than 7.5%, most preferably not more than 5.0% and in particularnot more than 2.5%.

In connection with the pharmacologically active ingredient, the EVApolymer, the optionally present additional prolonged release matrixmaterial and the optional pharmaceutical excipients, the term “stable”preferably means that the pharmaceutical dosage forms satisfy therequirements of EMEA concerning shelf-life of pharmaceutical products.

In a preferred embodiment, the additional prolonged release matrixmaterial exerts an influence on the release profile of thepharmacologically active ingredient. According to this embodiment, apharmaceutical dosage form according to the invention comprising apharmacologically active ingredient, an EVA polymer and an additionalprolonged release matrix material preferably exhibits an increasedrelease rate of the pharmacologically active ingredient than apharmaceutical dosage form comprising the same types and amounts of thepharmacologically active ingredient and the EVA polymer but notcontaining any additional prolonged release matrix material.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is adapted for administration once daily. In anotherpreferred embodiment, the pharmaceutical dosage form according to theinvention is adapted for administration twice daily. In still anotherpreferred embodiment, the pharmaceutical dosage form according to theinvention is adapted for administration thrice daily. In yet anotherpreferred embodiment, the pharmaceutical dosage form according to theinvention is adapted for administration more frequently than thricedaily, for example 4 times daily, 5 times daily, 6 times daily, 7 timesdaily or 8 times daily.

For the purpose of the specification, “twice daily” means equal ornearly equal time intervals, i.e., about every 12 hours, or differenttime intervals, e.g., 8 and 16 hours or 10 and 14 hours, between theindividual administrations.

For the purpose of the specification, “thrice daily” means equal ornearly equal time intervals, i.e., about every 8 hours, or differenttime intervals, e.g., 6, 6 and 12 hours; or 7, 7 and 10 hours, betweenthe individual administrations.

The pharmaceutical dosage form according to the invention providestamper resistance in terms of resistance against solvent extraction,resistance against grinding, and resistance against dose-dumping inaqueous ethanol.

Preferably, the prolonged release matrix of the pharmaceutical dosageform according to the invention not only provides prolonged release ofthe pharmacologically active ingredient, but additionally providestamper resistance, i.e. resistance against solvent extraction,resistance against grinding, and resistance against dose-dumping inaqueous ethanol.

As used herein, the term “tamper resistant” refers to pharmaceuticaldosage forms that are resistant to conversion into a form suitable formisuse or abuse by conventional means, particular for nasal and/orintravenous administration.

In this regard, when the pharmaceutical dosage form is multiparticulate,as such it may be crushable by conventional means such as grinding in amortar or crushing by means of a hammer. However, when thepharmaceutical dosage form is multiparticulate, the particles whichcontain the pharmacologically active ingredient exhibit mechanicalproperties such that they cannot be pulverized by conventional means anyfurther. As the particles are of macroscopic size and contain thepharmacologically active ingredient, they cannot be administered nasallythereby rendering the pharmaceutical dosage form tamper resistant.

Further, when trying to disrupt the pharmaceutical dosage forms by meansof a hammer or mortar, the particles tend to adhere to one anotherthereby forming aggregates and agglomerates, respectively, which arelarger in size than the untreated particles.

The pharmaceutical dosage form according to the invention exhibitsresistance against solvent extraction. Preferably, the prolonged releasematrix provides the pharmaceutical dosage form according to theinvention with resistance against solvent extraction.

Preferably, when trying to tamper the pharmaceutical dosage form inorder to prepare a formulation suitable for abuse by intravenousadministration, the liquid part of the formulation that can be separatedfrom the remainder by means of a syringe at room temperature is as lessas possible, preferably it contains not more than 75 or 45 or 40 wt.-%,more preferably not more than 35 wt.-%, still more preferably not morethan 30 wt.-%, yet more preferably not more than 25 wt.-%, even morepreferably not more than 20 wt.-%, most preferably not more than 15wt.-% and in particular not more than 10 wt.-% of the originallycontained pharmacologically active ingredient.

Preferably, this property is tested by (i) dispensing a pharmaceuticaldosage form that is either intact or has been manually comminuted bymeans of two spoons in 5 ml of solvent, either purified water or aqueousethanol (40 vol. %), (ii) allowing the dispersion to stand for 10 min atroom temperature, (iii) drawing up the hot liquid into a syringe (needle21 G equipped with a cigarette filter), and (iv) determining the amountof the pharmacologically active ingredient contained in the liquidwithin the syringe.

The pharmaceutical dosage form according to the invention exhibitsresistance against grinding. Preferably, the prolonged release matrixprovides the pharmaceutical dosage form according to the invention withresistance against grinding.

Preferably, when a pharmaceutical dosage form according to the inventionis treated with a commercial coffee mill, preferably type Bosch MKM6000,180W, Typ KM13 for 2 minutes, 42±17.5 wt.-%, more preferably 42±15wt.-%, still more preferably 42±12.5 wt.-%, yet more preferably 42±10wt.-%, even more preferably 42±7.5 wt.-%, most preferably 42±5 wt.-%,and in particular 42±2.5 wt.-%, of the total weight of the thus obtainedmaterial does not pass a sieve having a mesh size of 1.000 mm.

Preferably, when a pharmaceutical dosage form according to the inventionis treated with a commercial coffee mill, preferably type Bosch MKM6000,180W, Typ KM13, for 2 minutes, 57±17.5 wt.-%, more preferably 57±15wt.-%, still more preferably 57±12.5 wt.-%, yet more preferably 57±10wt.-%, even more preferably 57±7.5 wt.-%, most preferably 57±5 wt.-%,and in particular 57±2.5 wt.-%, of the total weight of the thus obtainedmaterial does not pass a sieve having a mesh size of 1.000 mm.

Preferably, when a pharmaceutical dosage form according to the inventionis treated with a commercial coffee mill, preferably type Bosch MKM6000,180W, Typ KM13, for 2 minutes, at least 50 wt.-%, more preferably atleast 55 wt.-%, still more preferably at least 60 wt.-%, yet morepreferably at least 65 wt.-%, even more preferably at least 70 wt.-%,most preferably at least 75 wt.-%, and in particular at least 80 wt.-%,of the total weight of the thus obtained material does not pass a sievehaving a mesh size of 1.000 mm.

Particle size distributions of the ground pharmaceutical dosage form arepreferably determined by sieve analysis.

In a preferred embodiment, more than 55%, more preferably more than 60%,still more preferably more than 65%, yet more preferably more than 70%,most preferably 75% and in particular more than 80% of the particles ofthe ground pharmaceutical dosage form have a size in the range of from0.2 to 3.3 nm, more preferably of from 0.4 to 3.1 nm, most preferably offrom 0.6 to 2.9 and in particular of from 0.7 to 2.8 nm.

Preferred particle distributions P₁ to P₄ are summarized in the tablebelow:

particle size amount in % [nm] P₁ P₂ P₃ P₄ <0.045 0.5 ± 0.4  0.1 ± 0.09 0.3 ± 0.29  0.3 ± 0.29 0.045-0.063 0.5 ± 0.4  0.3 ± 0.29  0.3 ± 0.29 0.3 ± 0.29 0.063-0.090 0.5 ± 0.4  0.3 ± 0.29  0.3 ± 0.29 1.0 ± 0.90.090-0.125 0.5 ± 0.4  0.3 ± 0.29  0.3 ± 0.29 1.0 ± 0.9 0.125-0.180 0.5± 0.4 3.0 ± 2.9 2.0 ± 1.5 2.0 ± 1.5 0.180-0.250 1.5 ± 1.4 1.0 ± 0.8 2.0± 1.5 1.0 ± 0.9 0.250-0.355 4.0 ± 3.5 5.0 ± 4.0 4.0 ± 3.5 3.5 ± 2.50.355-0.500 7.0 ± 6.0 5.0 ± 4.0 6.0 ± 4.5 7.0 ± 6.0 0.500-0.710 11.0 ±8.0  9.0 ± 7.0 11.0 ± 8.0  10.0 ± 7.0  0.710-1.000 15.0 ± 12.0 10.0 ±7.0  17.0 ± 14.0 18.0 ± 15.0 1.000-1.400 20.0 ± 17.0 18.0 ± 15.0 23.0 ±20.0 28.0 ± 25.0 1.400-2.000 23.0 ± 20.0 19.0 ± 16.0 12.0 ± 9.0  18.0 ±15.0 2.000-2.800 13.0 ± 10.0 16.0 ± 13.0 13.0 ± 10.0 11.0 ± 8.0 2.800-4.000 1.0 ± 0.8 14.0 ± 11.0 12.0 ± 9.0   0.3 ± 0.29 >4.00   0.5 ±0.45  0.3 ± 0.29  0.3 ± 0.29  0.5 ± 0.45

Further preferred particle distributions P₅ to P₈ are summarized in thetable below:

particle size amount in % [nm] P₅ P₆ P₇ P₈ <0.045  0.3 ± 0.29  0.3 ±0.29  0.3 ± 0.29  0.3 ± 0.29 0.045-0.063  0.3 ± 0.29  0.3 ± 0.29 1.0 ±0.9  0.3 ± 0.29 0.063-0.090  0.3 ± 0.29  0.3 ± 0.29 1.5 ± 1.0  0.3 ±0.29 0.090-0.125  0.3 ± 0.29 1.0 ± 0.9 3.5 ± 3.0  0.3 ± 0.29 0.125-0.1801.0 ± 0.9 1.0 ± 0.9 1.0 ± 0.9 3.0 ± 2.9 0.180-0.250 2.0 ± 1.5 1.0 ± 0.9 0.3 ± 0.29 1.5 ± 1.0 0.250-0.355 5.0 ± 4.0 3.0 ± 2.9  0.3 ± 0.29 2.0 ±1.9 0.355-0.500 7.0 ± 6.0 7.0 ± 6.0 5.0 ± 4.0 1.0 ± 0.9 0.500-0.710 13.0± 10.0 9.0 ± 7.0 8.0 ± 6.0 3.5 ± 2.5 0.710-1.000 18.0 ± 15.0 13.0 ± 10.055.0 ± 30.0 19.5 ± 15.0 1.000-1.400 25.0 ± 22.0 20.0 ± 17.0 6.5 ± 5.070.1 ± 50.0 1.400-2.000 10.0 ± 7.0  22.0 ± 19.0 13.0 ± 10.0 2.0 ± 1.92.000-2.800 14.0 ± 11.0 12.0 ± 9.0  3.0 ± 2.9  0.3 ± 0.29 2.800-4.0004.0 ± 3.5 9.0 ± 7.0 2.0 ± 1.9  0.3 ± 0.29 >4.00   0.3 ± 0.29  0.5 ± 0.4513.0 ± 10.0 1.5 ± 1.0

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is monolithic and has a breaking strength of at least 300N or, when the pharmaceutical dosage form according to the invention ismultiparticulate, at least a fraction of the individual particles have abreaking strength of at least 300 N.

Preferably, the mechanical properties, particularly the breakingstrength, substantially relies on the presence and spatial distributionof the EVA polymer (the prolonged release matrix material), although itsmere presence does typically not suffice in order to achieve saidproperties. The advantageous mechanical properties may not automaticallybe achieved by simply processing pharmacologically active ingredient,EVA polymer (the prolonged release matrix material), optionallyadditional prolonged release matrix material, and optionally furtherexcipients by means of conventional methods for the preparation ofpharmaceutical dosage forms. In fact, usually suitable apparatuses mustbe selected for the preparation and critical processing parameters mustbe adjusted, particularly pressure/force, temperature and time. Thus,even if conventional apparatuses are used, the process protocols usuallymust be adapted in order to meet the required criteria.

In general, the desired properties may be obtained only if, duringpreparation of the pharmaceutical dosage form,

-   -   suitable components    -   in suitable amounts        are exposed to    -   a sufficient pressure    -   at a sufficient temperature    -   for a sufficient period of time.

Thus, regardless of the apparatus used, the process protocols must beadapted in order to meet the required criteria. Therefore, the breakingstrength is separable from the composition.

The pharmaceutical dosage form or, when it is multiparticulate, theparticles according to the invention which contain the pharmacologicallyactive ingredient preferably have a breaking strength of at least 300 N,at least 400 N, or at least 500 N, preferably at least 600 N, morepreferably at least 700 N, still more preferably at least 800 N, yetmore preferably at least 1000 N, most preferably at least 1250 N and inparticular at least 1500 N.

When the pharmaceutical dosage form is an oblong tablet, preferably thebreaking strengths of the pharmaceutical dosage form across andlengthwise are each at least 200 N, at least 300 N, at least 400 N, atleast 500 N, at least 600 N, at least 700 N, at least 800 N, at least1000 N or at least 1500 N.

The “breaking strength” (resistance to crushing) of a pharmaceuticaldosage form and of a particle is known to the skilled person. In thisregard it can be referred to, e.g., W. A. Ritschel, Die Tablette, 2.Auflage, Editio Cantor Verlag Aulendorf, 2002; H Liebermann et al.,Pharmaceutical dosage forms: Pharmaceutical dosage forms, Vol. 2,Informa Healthcare; 2 edition, 1990; and Encyclopedia of PharmaceuticalTechnology, Informa Healthcare; 1 edition.

For the purpose of specification, the breaking strength is preferablydefined as the amount of force that is necessary in order to fracture apharmaceutical dosage form and a particle, respectively (=breakingforce). Therefore, for the purpose of specification, a pharmaceuticaldosage form and a particle, respectively, does preferably not exhibitthe desired breaking strength when it breaks, i.e., is fractured into atleast two independent parts that are separated from one another. Inanother preferred embodiment, however, the pharmaceutical dosage formand particle, respectively, is regarded as being broken if the forcedecreases by 25% (threshold value) of the highest force measured duringthe measurement (see below).

The pharmaceutical dosage forms and particles, respectively, accordingto the invention are distinguished from conventional pharmaceuticaldosage forms and particles, respectively, in that due to their breakingstrength, they cannot be pulverized by the application of force withconventional means, such as for example a pestle and mortar, a hammer, amallet or other usual means for pulverization, in particular devicesdeveloped for this purpose (pharmaceutical dosage form crushers). Inthis regard “pulverization” means crumbling into small particles.Avoidance of pulverization virtually rules out oral or parenteral, inparticular intravenous or nasal abuse.

Conventional pharmaceutical dosage forms and particles, respectively,typically have a breaking strength well below 200 N.

The breaking strength of conventional round pharmaceutical dosageforms/particles may be estimated according to the following empiricalformula:Breaking Strength [in N]=10×Diameter of pharmaceutical dosageform/particle [in mm].

Thus, according to said empirical formula, a round pharmaceutical dosageform/particle having a breaking strength of at least 300 N would requirea diameter of at least 30 mm. Such a particle, however, could not beswallowed, let alone a pharmaceutical dosage form containing a pluralityof such particles. The above empirical formula preferably does not applyto the pharmaceutical dosage form and particles, respectively, accordingto the invention, which are not conventional but rather special.

Further, the actual mean chewing force is about 220 N (cf., e.g., P. A.Proeschel et al., J Dent Res, 2002, 81(7), 464-468). This means thatconventional pharmaceutical dosage forms and particle, respectively,having a breaking strength well below 200 N may be crushed uponspontaneous chewing, whereas the pharmaceutical dosage forms andparticles, respectively, according to the invention may preferably not.

Still further, when applying a gravitational acceleration of about 9.81m/s², 300 N correspond to a gravitational force of more than 30 kg, i.e.the pharmaceutical dosage form and particle, respectively, according tothe invention can preferably withstand a weight of more than 30 kgwithout being pulverized.

Methods for measuring the breaking strength are known to the skilledartisan. Suitable devices are commercially available.

For example, the breaking strength (resistance to crushing) can bemeasured in accordance with the Eur. Ph. 5.0, 2.9.8 or 6.0, 2.09.08“Resistance to Crushing of Pharmaceutical dosage forms”. The particlesmay be subjected to the same or similar breaking strength test as thepharmaceutical dosage form. The test is intended to determine, underdefined conditions, the resistance to crushing of pharmaceutical dosageforms and individual particles, respectively, measured by the forceneeded to disrupt them by crushing. The apparatus consists of 2 jawsfacing each other, one of which moves towards the other. The flatsurfaces of the jaws are perpendicular to the direction of movement. Thecrushing surfaces of the jaws are flat and larger than the zone ofcontact with the pharmaceutical dosage form and individual particle,respectively. The apparatus is calibrated using a system with aprecision of 1 Newton. The pharmaceutical dosage form and particle,respectively, is placed between the jaws, taking into account, whereapplicable, the shape, the break-mark and the inscription; for eachmeasurement the pharmaceutical dosage form and particle, respectively,is oriented in the same way with respect to the direction of applicationof the force (and the direction of extension in which the breakingstrength is to be measured). The measurement is carried out on 10pharmaceutical dosage forms and particles, respectively, taking carethat all fragments have been removed before each determination. Theresult is expressed as the mean, minimum and maximum values of theforces measured, all expressed in Newton.

A similar description of the breaking strength (breaking force) can befound in the USP. The breaking strength can alternatively be measured inaccordance with the method described therein where it is stated that thebreaking strength is the force required to cause a pharmaceutical dosageform and particle, respectively, to fail (i.e., break) in a specificplane. The pharmaceutical dosage forms and particles, respectively, aregenerally placed between two platens, one of which moves to applysufficient force to the pharmaceutical dosage form and particle,respectively, to cause fracture. For conventional, round (circularcross-section) pharmaceutical dosage forms and particles, respectively,loading occurs across their diameter (sometimes referred to as diametralloading), and fracture occurs in the plane. The breaking force ofpharmaceutical dosage forms and particles, respectively, is commonlycalled hardness in the pharmaceutical literature; however, the use ofthis term is misleading. In material science, the term hardness refersto the resistance of a surface to penetration or indentation by a smallprobe. The term crushing strength is also frequently used to describethe resistance of pharmaceutical dosage forms and particle,respectively, to the application of a compressive load. Although thisterm describes the true nature of the test more accurately than doeshardness, it implies that pharmaceutical dosage forms and particles,respectively, are actually crushed during the test, which is often notthe case.

Alternatively, the breaking strength (resistance to crushing) can bemeasured in accordance with WO 2008/107149, which can be regarded as amodification of the method described in the Eur. Ph. The apparatus usedfor the measurement is preferably a “Zwick Z 2.5” materials tester,F_(max)=2.5 kN with a maximum draw of 1150 mm, which should be set upwith one column and one spindle, a clearance behind of 100 mm and a testspeed adjustable between 0.1 and 800 mm/min together with testControlsoftware. Measurement is performed using a pressure piston with screw-ininserts and a cylinder (diameter 10 mm), a force transducer, F_(max)=1kN, diameter=8 mm, class 0.5 from 10 N, class 1 from 2 N to ISO 7500-1,with manufacturer's test certificate M according to DIN 55350-18 (Zwickgross force F_(max)=1.45 kN) (all apparatus from Zwick GmbH & Co. KG,Ulm, Germany) with Order No BTC-FR 2.5 TH. D09 for the tester, Order NoBTC-LC 0050N. P01 for the force transducer, Order No BO 70000 S06 forthe centering device.

In a preferred embodiment, the pharmaceutical dosage form and particle,respectively, is regarded as being broken if it is fractured into atleast two separate pieces.

The pharmaceutical dosage form and particle, respectively, according tothe invention preferably exhibit mechanical strength over a widetemperature range, in addition to the breaking strength (resistance tocrushing) optionally also sufficient hardness, impact resistance, impactelasticity, tensile strength and/or modulus of elasticity, optionallyalso at low temperatures (e.g. below −24° C., below −40° C. or possiblyeven in liquid nitrogen), for it to be virtually impossible to pulverizeby spontaneous chewing, grinding in a mortar, pounding, etc. Thus,preferably, the comparatively high breaking strength of thepharmaceutical dosage form and particle, respectively, according to theinvention is maintained even at low or very low temperatures, e.g., whenthe pharmaceutical dosage form is initially chilled to increase itsbrittleness, for example to temperatures below −25° C., below −40° C. oreven in liquid nitrogen.

The pharmaceutical dosage form and particle, respectively, according tothe invention is characterized by a certain degree of breaking strength.This does not mean that it must also exhibit a certain degree ofhardness. Hardness and breaking strength are different physicalproperties. Therefore, the tamper resistance of the pharmaceuticaldosage form does not necessarily depend on the hardness of thepharmaceutical dosage form and particle, respectively. For instance, dueto its breaking strength, impact strength, elasticity modulus andtensile strength, respectively, the pharmaceutical dosage form andparticle, respectively, can preferably be deformed, e.g. plastically,when exerting an external force, for example using a hammer, but cannotbe pulverized, i.e., crumbled into a high number of fragments. In otherwords, the pharmaceutical dosage form and particle, respectively,according to the invention are characterized by a certain degree ofbreaking strength, but not necessarily also by a certain degree of formstability.

Therefore, in the meaning of the specification, a pharmaceutical dosageform and particle, respectively, that is deformed when being exposed toa force in a particular direction of extension but that does not break(plastic deformation or plastic flow) is preferably to be regarded ashaving the desired breaking strength in said direction of extension.

Preferred pharmaceutical dosage forms and particles, respectively, arethose having a suitable tensile strength as determined by a test methodcurrently accepted in the art. Further preferred pharmaceutical dosageforms and particles, respectively, are those having a Young's Modulus asdetermined by a test method of the art. Still further preferredpharmaceutical dosages form and particles, respectively, are thosehaving an acceptable elongation at break.

The pharmaceutical dosage form according to the invention exhibitsresistance against dose-dumping in aqueous ethanol. Preferably, theprolonged release matrix provides the pharmaceutical dosage formaccording to the invention with resistance against dose-dumping inaqueous ethanol.

The pharmaceutical dosage form can be tested in vitro usingethanol/simulated gastric fluid of 0%, 20% and 40% to evaluate alcoholextractability. Testing is preferably performed using standardprocedures, e.g. USP Apparatus 1 (basket) or USP Apparatus 2 (paddle) ate.g. 50 rpm or 75 rpm in e.g. 500 ml of media at 37° C., using a PerkinElmer UV/VIS Spectrometer Lambda 20, UV at an appropriate wavelength fordetection of the pharmacologically active ingredient present therein.Sample time points preferably include 0.5 and 1 hour.

Preferably, when comparing the in vitro release profile at 37° C. insimulated gastric fluid with the in vitro release profile inethanol/simulated gastric fluid (40 vol.-%) at 37° C., the in vitrorelease in ethanol/simulated gastric fluid (40 vol.-%) is preferably notsubstantially accelerated compared to the in vitro release in simulatedgastric fluid. Preferably, in this regard “substantially” means that atany given time point the in vitro release in ethanol/simulated gastricfluid (40 vol.-%) relatively deviates from the in vitro release insimulated gastric fluid by not more than +25%, more preferably not morethan +20%, still more preferably not more than +15%, yet more preferablynot more than +10%, even more preferably not more than +7.5%, mostpreferably not more than +5.0% and in particular not more than +2.5%.

A substantial relative acceleration of the in vitro release inethanol/simulated gastric fluid (40 vol.-%) compared to the in vitrorelease in simulated gastric fluid is to be prevented according to theinvention. However, a substantial relative deceleration of the in vitrorelease in ethanol/simulated gastric fluid (40 vol.-%) compared to thein vitro release in simulated gastric fluid, e.g., a relative deviationby −25% or more, may be possible and can even be desirable.

The pharmacologically active ingredient having psychotropic action isnot particularly limited.

For the purpose of definition, a pharmacologically active ingredienthaving psychotropic action is preferably meant to refer to anypharmacologically active ingredient which crosses the blood-brainbarrier and acts primarily upon the central nervous system where itaffects brain function, resulting in alterations in perception, mood,consciousness, cognition, and behavior.

In a preferred embodiment, the pharmaceutical dosage form contains onlya single pharmacologically active ingredient. In another preferredembodiment, the pharmaceutical dosage form contains a combination of twoor more pharmacologically active ingredients.

Preferably, the pharmaceutical dosage form according to the inventioncomprises a pharmacologically active ingredient having potential forabuse and potential for dose dumping in ethanol. Active ingredients withpotential for being abused are known to the person skilled in the artand comprise e.g. tranquilizers, stimulants, barbiturates, narcotics,opioids or opioid derivatives.

Preferably, the pharmacologically active ingredient is selected from thegroup consisting of opiates, opioids, stimulants, tranquilizers, othernarcotics and anesthetics. Preferably, the pharmacologically activeingredient is selected from the group consisting of ethers; halogenatedhydrocarbons; pain barbiturates; and barbiturates in combination withother drugs; opioid anesthetics; or any other general anesthetics.

In a particularly preferred embodiment, the pharmacologically activeingredient is an opioid or a physiologically acceptable salt thereof.

According to the ATC index, opioids are divided into natural opiumalkaloids, phenylpiperidine derivatives, diphenylpropylaminederivatives, benzomorphan derivatives, oripavine derivatives, morphinanderivatives and others.

The following opiates, opioids, tranquillizers, anesthetics or othernarcotics are substances with a psychotropic action, i.e. have apotential of abuse, and hence are preferably contained in thepharmaceutical dosage form and the particles, respectively: alfentanil,allobarbital, allylprodine, alphaprodine, alprazolam, amfepramone,amphetamine, amphetaminil, amobarbital, anileridine, apocodeine,axomadol, barbital, bemidone, benzylmorphine, bezitramide, bromazepam,brotizolam, buprenorphine, butobarbital, butorphanol, camazepam,carfentanil, cathine/D-norpseudoephedrine, chlordiazepoxide, clobazamclofedanol, clonazepam, clonitazene, clorazepate, clotiazepam,cloxazolam, cocaine, codeine, cyclobarbital, cyclorphan, cyprenorphine,delorazepam, desomorphine, dextromoramide, dextropropoxyphene, dezocine,diampromide, diamorphone, diazepam, dihydrocodeine, dihydromorphine,dihydromorphone, dimenoxadol, dimephetamol, dimethylthiambutene,dioxaphetylbutyrate, dipipanone, dronabinol, eptazocine, estazolam,ethoheptazine, ethylmethylthiambutene, ethyl loflazepate, ethylmorphine,etonitazene, etorphine, faxeladol, fencamfamine, fenethylline,fenpipramide, fenproporex, fentanyl, fludiazepam, flunitrazepam,flurazepam, halazepam, haloxazolam, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, hydroxymethylmorphinan, ketamine,(S)-ketamine, ketazolam, ketobemidone, levacetylmethadol (LAAM),levomethadone, levorphanol, levophenacylmorphane, levoxemacin,lisdexamfetamine dimesylate, lofentanil, loprazolam, lorazepam,lormetazepam, mazindol, medazepam, mefenorex, meperidine, meprobamate,metapon, meptazinol, metazocine, methylmorphine, metamphetamine,methadone, methaqualone, 3-methylfentanyl, 4-methylfentanyl,methylphenidate, methylphenobarbital, methyprylon, metopon, midazolam,modafinil, morphine, myrophine, nabilone, nalbuphene, nalorphine,narceine, nicomorphine, nimetazepam, nitrazepam, nordazepam,norlevorphanol, normethadone, normorphine, norpipanone, opium, oxazepam,oxazolam, oxyco done, oxymorphone, Papaver somniferum, papaveretum,pernoline, pentazocine, pentobarbital, pethidine, phenadoxone,phenomorphane, phenazocine, phenoperidine, piminodine, pholcodeine,phenmetrazine, phenobarbital, phentermine, pinazepam, pipradrol,piritramide, prazepam, profadol, proheptazine, promedol, properidine,propoxyphene, remifentanil, secbutabarbital, secobarbital, sufentanil,tapentadol, temazepam, tetrazepam, tilidine (cis and trans), tramadol,triazolam, vinylbital,N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)-propionamide,(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol,(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol,(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,(2R,3R)-1-dimethylamino-3 (3-methoxyphenyl)-2-methyl-pentan-3-ol,(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,preferably as racemate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(4-isobutyl-phenyl)propionate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(6-methoxy-naphthalen-2-yl)propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(4-isobutyl-phenyl)propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(6-methoxy-naphthalen-2-yl)propionate,(RR—SS)-2-acetoxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-4-chloro-2-hydroxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-4-methyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-4-methoxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-5-nitro-benzoicacid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2′,4′-difluoro-3-hydroxy-biphenyl-4-carboxylic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, andcorresponding stereoisomeric compounds, in each case the correspondingderivatives thereof, physiologically acceptable enantiomers,stereoisomers, diastereomers and racemates and the physiologicallyacceptable derivatives thereof, e.g. ethers, esters or amides, and ineach case the physiologically acceptable compounds thereof, inparticular the acid or base addition salts thereof and solvates, e.g.hydrochlorides.

In a preferred embodiment, the pharmacologically active ingredient isselected from the group consisting of tramadol, tapentadol, faxeladoland axomadol.

In another preferred embodiment, the pharmacologically active ingredientis selected from the group consisting of DPI-125, M6G (CE-04-410),ADL-5859, CR-665, NRP290 and sebacoyl dinalbuphine ester.

In still another preferred embodiment, the pharmacologically activeingredient is selected from the group consisting of oxycodone,oxymorphone, hydrocodone, hydromorphone, taramdol, tapentadol, morphine,buprenorphine and the physiologically acceptable salts thereof.

In yet another preferred embodiment, the pharmacologically activeingredient is selected from the group consisting of1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole,particularly its hemicitrate;1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrano[3,4-b]indole,particularly its citrate; and1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrano[3,4-b]-6-fluoroindole,particularly its hemicitrate. These compounds are known from, e.g., WO2004/043967, WO 2005/066183.

The pharmacologically active ingredient may be present in form of aphysiologically acceptable salt, e.g. physiologically acceptable acidaddition salt.

Physiologically acceptable acid addition salts comprise the acidaddition salt forms which can conveniently be obtained by treating thebase form of the active ingredient with appropriate organic andinorganic acids. Active ingredients containing an acidic proton may beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. The termaddition salt also comprises the hydrates and solvent addition formswhich the active ingredients are able to form. Examples of such formsare e.g. hydrates, alcoholates and the like.

It has been surprisingly found that the content of the pharmacologicallyactive ingredient in the pharmaceutical dosage form and in theparticles, respectively, can be optimized in order to provide the bestcompromise between tamper-resistance, disintegration time and drugrelease, drug load, processability (especially pharmaceutical dosageformability) and patient compliance.

The pharmacologically active ingredient is present in the pharmaceuticaldosage form in a therapeutically effective amount. The amount thatconstitutes a therapeutically effective amount varies according to theactive ingredients being used, the condition being treated, the severityof said condition, the patient being treated, and the frequency ofadministration.

The content of the pharmacologically active ingredient in thepharmaceutical dosage form is not limited. The dose of thepharmacologically active ingredient which is adapted for administrationpreferably is in the range of 0.1 mg to 500 mg, more preferably in therange of 1.0 mg to 400 mg, even more preferably in the range of 5.0 mgto 300 mg, and most preferably in the range of 10 mg to 250 mg. In apreferred embodiment, the total amount of the pharmacologically activeingredient that is contained in the pharmaceutical dosage form is withinthe range of from 0.01 to 200 mg, more preferably 0.1 to 190 mg, stillmore preferably 1.0 to 180 mg, yet more preferably 1.5 to 160 mg, mostpreferably 2.0 to 100 mg and in particular 2.5 to 80 mg.

Preferably, the content of the pharmacologically active ingredient iswithin the range of from 0.01 to 80 wt.-%, more preferably 0.1 to 50wt.-%, still more preferably 1 to 35 wt.-%, based on the total weight ofthe pharmaceutical dosage form.

In a preferred embodiment, the content of pharmacologically activeingredient is within the range of from 5.0±4.5 wt.-%, or 7.5±7.0 wt.-%,or 10±9.0 wt.-%, or 12.5±12.0 wt.-%, or 15±14 wt.-%, or 17.5±17.0 wt.-%,or 20±19 wt.-%, or 22.5±22.0 wt.-%, or 25±24 wt.-%; more preferably5.0±4.0 wt.-%, or 7.5±6.0 wt.-%, or 10±8.0 wt.-%, or 12.5±12.0 wt.-%, or15±12 wt.-%, or 17.5±15.0 wt.-%, or 20±19 wt.-%, or 22.5±22.0 wt.-%, or25±24 wt.-%; still more preferably 5.0±3.5 wt.-%, or 7.5±5.0 wt.-%, or10±7.0 wt.-%, or 12.5±10.0 wt.-%, or 15±10 wt.-%, or 17.5±13.0 wt.-%, or20±17 wt.-%, or 22.5±19.0 wt.-%, or 25±21 wt.-%; yet more preferably5.0±3.0 wt.-%, or 7.5±4.0 wt.-%, or 10±6.0 wt.-%, or 12.5±8.0 wt.-%, or15±8.0 wt.-%, or 17.5±11.0 wt.-%, or 20±15 wt.-%, or 22.5±16.0 wt.-%, or25±18 wt.-%; even more preferably 5.0±2.5 wt.-%, or 7.5±3.0 wt.-%, or10±5.0 wt.-%, or 12.5±6.0 wt.-%, or 15±6.0 wt.-%, or 17.5±9.0 wt.-%, or20±13 wt.-%, or 22.5±13.0 wt.-%, or 25±15 wt.-%; most preferably 5.0±2.0wt.-%, or 7.5±2.0 wt.-%, or 10±4.0 wt.-%, or 12.5±4.0 wt.-%, or 15±4.0wt.-%, or 17.5±7.0 wt.-%, or 20±11 wt.-%, or 22.5±10.0 wt.-%, or 25±12wt.-%; and in particular 5.0±1.5 wt.-%, or 7.5±1.0 wt.-%, or 10±3.0wt.-%, or 12.5±2.0 wt.-%, or 15±2.0 wt.-%, or 17.5±5.0 wt.-%, or 20±9wt.-%, or 22.5±7.0 wt.-%, or 25±9 wt.-%; in each case either based onthe total weight of the pharmaceutical dosage form or, when thepharmaceutical dosage form is multiparticulate, based on the totalweight of the particles that contain the pharmacologically activeingredient.

In another preferred embodiment, the content of pharmacologically activeingredient is within the range of from 20±6 wt.-%, more preferably 20±5wt.-%, still more preferably 20±4 wt.-%, most preferably 20±3 wt.-%, andin particular 20±2 wt.-%, either based on the total weight of thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, based on the total weight of the particles thatcontain the pharmacologically active ingredient. In still anotherpreferred embodiment, the content of pharmacologically active ingredientis within the range of from 25±6 wt.-%, more preferably 25±5 wt.-%,still more preferably 25±4 wt.-%, most preferably 25±3 wt.-%, and inparticular 25±2 wt.-%, either based on the total weight of thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, based on the total weight of the particles thatcontain the pharmacologically active ingredient. In yet anotherpreferred embodiment, the content of pharmacologically active ingredientis within the range of from 30±6 wt.-%, more preferably 30±5 wt.-%,still more preferably 30±4 wt.-%, most preferably 30±3 wt.-%, and inparticular 30±2 wt.-%, either based on the total weight of thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, based on the total weight of the particles thatcontain the pharmacologically active ingredient. In even anotherpreferred embodiment, the content of pharmacologically active ingredientis within the range of from 34±6 wt.-%, more preferably 34±5 wt.-%,still more preferably 34±4 wt.-%, most preferably 34±3 wt.-%, and inparticular 34±2 wt.-%, either based on the total weight of thepharmaceutical dosage form or, when the pharmaceutical dosage form ismultiparticulate, based on the total weight of the particles thatcontain the pharmacologically active ingredient. In a further preferredembodiment, the content of pharmacologically active ingredient is withinthe range of from 40±6 wt.-%, more preferably 40±5 wt.-%, still morepreferably 40±4 wt.-%, most preferably 40±3 wt.-%, and in particular40±2 wt.-%, either based on the total weight of the pharmaceuticaldosage form or, when the pharmaceutical dosage form is multiparticulate,based on the total weight of the particles that contain thepharmacologically active ingredient.

The skilled person may readily determine an appropriate amount ofpharmacologically active ingredient to include in a pharmaceuticaldosage form. For instance, in the case of analgesics, the total amountof pharmacologically active ingredient present in the pharmaceuticaldosage form is that sufficient to provide analgesia. The total amount ofpharmacologically active ingredient administered to a patient in a dosewill vary depending on numerous factors including the nature of thepharmacologically active ingredient, the weight of the patient, theseverity of the pain, the nature of other therapeutic agents beingadministered etc.

In a preferred embodiment, the pharmacologically active ingredient iscontained in the pharmaceutical dosage form in an amount of 7.5±5 mg,10±5 mg, 20±5 mg, 30±5 mg, 40±5 mg, 50±5 mg, 60±5 mg, 70±5 mg, 80±5 mg,90±5 mg, 100±5 mg, 110±5 mg, 120±5 mg, 130±5, 140±5 mg, 150±5 mg, 160±5mg, 170±5 mg, 180±5 mg, 190±5 mg, 200±5 mg, 210±5 mg, 220±5 mg, 230±5mg, 240±5 mg, 250±5 mg, 260±5 mg, 270±5 mg, 280±5 mg, 290±5 mg, or 300±5mg. In another preferred embodiment, the pharmacologically activeingredient is contained in the pharmaceutical dosage form in an amountof 5±2.5 mg, 7.5±2.5 mg, 10±2.5 mg, 15±2.5 mg, 20±2.5 mg, 25±2.5 mg,30±2.5 mg, 35±2.5 mg, 40±2.5 mg, 45±2.5 mg, 50±2.5 mg, 55±2.5 mg, 60±2.5mg, 65±2.5 mg, 70±2.5 mg, 75±2.5 mg, 80±2.5 mg, 85±2.5 mg, 90±2.5 mg,95±2.5 mg, 100±2.5 mg, 105±2.5 mg, 110±2.5 mg, 115±2.5 mg, 120±2.5 mg,125±2.5 mg, 130±2.5 mg, 135±2.5 mg, 140±2.5 mg, 145±2.5 mg, 150±2.5 mg,155±2.5 mg, 160±2.5 mg, 165±2.5 mg, 170±2.5 mg, 175±2.5 mg, 180±2.5 mg,185±2.5 mg, 190±2.5 mg, 195±2.5 mg, 200±2.5 mg, 205±2.5 mg, 210±2.5 mg,215±2.5 mg, 220±2.5 mg, 225±2.5 mg, 230±2.5 mg, 235±2.5 mg, 240±2.5 mg,245±2.5 mg, 250±2.5 mg, 255±2.5 mg, 260±2.5 mg, or 265±2.5 mg.

In a particularly preferred embodiment, the pharmacologically activeingredient is oxycodone, preferably its HCl salt, and the pharmaceuticaldosage form is adapted for administration twice daily. In thisembodiment, the pharmacologically active ingredient is preferablycontained in the pharmaceutical dosage form in a total amount of from 1to 80 mg. In another particularly preferred embodiment, thepharmacologically active ingredient is oxycodone, preferably its HClsalt, and the pharmaceutical dosage form is adapted for administrationonce daily. In this embodiment, the pharmacologically active ingredientis preferably contained in the pharmaceutical dosage form in a totalamount of from 2 to 320 mg.

In another particularly preferred embodiment, the pharmacologicallyactive ingredient is oxymorphone, preferably its HCl salt, and thepharmaceutical dosage form is adapted for administration twice daily. Inthis embodiment, the pharmacologically active ingredient is preferablycontained in the pharmaceutical dosage form in a total amount of from 5to 40 mg. In another particularly preferred embodiment, thepharmacologically active ingredient is oxymorphone, preferably its HClsalt, and the pharmaceutical dosage form is adapted for administrationonce daily. In this embodiment, the pharmacologically active ingredientis preferably contained in the pharmaceutical dosage form in a totalamount of from 10 to 80 mg.

In another particularly preferred embodiment, the pharmacologicallyactive ingredient is tapentadol, preferably its HCl salt, and thepharmaceutical dosage form is adapted for administration once daily ortwice daily. In this embodiment, the pharmacologically active ingredientis preferably contained in the pharmaceutical dosage form in a totalamount of from 25 to 250 mg.

In still another particularly preferred embodiment, thepharmacologically active ingredient is hydromorphone, preferably its HClsalt, and the pharmaceutical dosage form is adapted for administrationtwice daily. In this embodiment, the pharmacologically active ingredientis preferably contained in the pharmaceutical dosage form in a totalamount of from 2 to 52 mg. In another particularly preferred embodiment,the pharmacologically active ingredient is hydromorphone, preferably itsHCl salt, and the pharmaceutical dosage form is adapted foradministration once daily. In this embodiment, the pharmacologicallyactive ingredient is preferably contained in the pharmaceutical dosageform in a total amount of from 4 to 104 mg.

In yet another particularly preferred embodiment, the pharmacologicallyactive ingredient is tramadol, preferably its HCl salt, and thepharmaceutical dosage form is adapted for administration twice daily. Inthis embodiment, the pharmacologically active ingredient is preferablycontained in the pharmaceutical dosage form in a total amount of from 5to 300 mg. In another particularly preferred embodiment, thepharmacologically active ingredient is tramadol, preferably its HClsalt, and the pharmaceutical dosage form is adapted for administrationonce daily. In this embodiment, the pharmacologically active ingredientis preferably contained in the pharmaceutical dosage form in a totalamount of from 10 to 500 mg.

In another particularly preferred embodiment, the pharmacologicallyactive ingredient is hydrocodone, preferably its HCl salt, and thepharmaceutical dosage form is adapted for administration twice daily. Inthis embodiment, the pharmacologically active ingredient is preferablycontained in the pharmaceutical dosage form in a total amount of from 5to 250 mg. In another particularly preferred embodiment, thepharmacologically active ingredient is hydrocodone, preferably its HClsalt, and the pharmaceutical dosage form is adapted for administrationonce daily. In this embodiment, the pharmacologically active ingredientis preferably contained in the pharmaceutical dosage form in a totalamount of from 5 to 250 mg.

In still another particularly preferred embodiment, thepharmacologically active ingredient is morphine, preferably its HCl orH₂SO₄ salt, and the pharmaceutical dosage form is adapted foradministration twice daily. In this embodiment, the pharmacologicallyactive ingredient is preferably contained in the pharmaceutical dosageform in a total amount of from 5 to 250 mg. In another particularlypreferred embodiment, the pharmacologically active ingredient ismorphine, preferably its HCl or H₂SO₄ salt, and the pharmaceuticaldosage form is adapted for administration once daily. In thisembodiment, the pharmacologically active ingredient is preferablycontained in the pharmaceutical dosage form in a total amount of from 5to 250 mg.

In another particularly preferred embodiment, the pharmacologicallyactive ingredient is buprenorphine, preferably its HCl salt, and thepharmaceutical dosage form is adapted for administration twice daily. Inthis embodiment, the pharmacologically active ingredient is preferablycontained in the pharmaceutical dosage form in a total amount of from 1to 12 mg. In another particularly preferred embodiment, thepharmacologically active ingredient is buprenorphine, preferably its HClsalt, and the pharmaceutical dosage form is adapted for administrationonce daily. In this embodiment, the pharmacologically active ingredientis preferably contained in the pharmaceutical dosage form in a totalamount of from 2 to 12 mg.

When the pharmaceutical dosage form is multiparticulate, the particlespresent in the pharmaceutical dosage forms according to the inventionpreferably comprise 3 to 75 wt.-% of pharmacologically activeingredient, more preferably 5 to 70 wt.-% of pharmacologically activeingredient, still more preferably 7.5 to 65 wt.-% of pharmacologicallyactive ingredient, based on the total weight of a particle.

When the pharmaceutical dosage form is multiparticulate, the content ofthe pharmacologically active ingredient is preferably at least 5 wt.-%,more preferably at least 10 wt.-%, still more preferably at least 15wt.-%, yet more preferably at least 20 wt.-%, most preferably at least25 wt.-% and in particular at least 30 wt.-%, based on the total weightof a particle.

When the pharmaceutical dosage form is multiparticulate, the content ofthe pharmacologically active ingredient is preferably at most 70 wt.-%,more preferably at most 65 wt.-%, still more preferably at most 60wt.-%, yet more preferably at most 55 wt.-%, most preferably at most 50wt.-%, based on the total weight of a particle.

In a preferred embodiment, when the pharmaceutical dosage form ismultiparticulate, the content of the pharmacologically active ingredientis within the range of 35±30 wt.-%, more preferably 35±25 wt.-%, stillmore preferably 35±20 wt.-%, yet more preferably 35±15 wt.-%, mostpreferably 35±10 wt.-%, and in particular 35±5 wt.-%, based on the totalweight of a particle. In another preferred embodiment, when thepharmaceutical dosage form is multiparticulate, the content of thepharmacologically active ingredient is within the range of 45±30 wt.-%,more preferably 45±25 wt.-%, still more preferably 45±20 wt.-%, yet morepreferably 45±15 wt.-%, most preferably 45±10 wt.-%, and in particular45±5 wt.-%, based on the total weight of a particle. In still anotherpreferred embodiment, when the pharmaceutical dosage form ismultiparticulate, the content of the pharmacologically active ingredientis within the range of 55±30 wt.-%, more preferably 55±25 wt.-%, stillmore preferably 55±20 wt.-%, yet more preferably 55±15 wt.-%, mostpreferably 55±10 wt.-%, and in particular 55±5 wt.-%, based on the totalweight of a particle.

The pharmacologically active ingredient that is included in thepreparation of the pharmaceutical dosage forms according to theinvention preferably has an average particle size of less than 500microns, still more preferably less than 300 microns, yet morepreferably less than 200 or 100 microns. There is no lower limit on theaverage particle size and it may be, for example, 50 microns. Theparticle size of pharmacologically active ingredients may be determinedby any technique conventional in the art, e.g. laser light scattering,sieve analysis, light microscopy or image analysis. Generally speakingit is preferable that the largest dimension of the pharmacologicallyactive ingredient particle be less than the size of the particles (e.g.less than the smallest dimension of the particles).

In a preferred embodiment, the pharmaceutical dosage form according tothe invention, preferably the particles, comprise an opioid (agonist) aswell as an opioid antagonist.

Any conventional opioid antagonist may be present, e.g. naltrexone ornaloxone or their pharmaceutically acceptable salts. Naloxone, includingits salts, is particularly preferred. The opioid antagonist may bepresent within the particles or within the matrix. Alternatively, opioidantagonist may be provided in separate particles to thepharmacologically active ingredients. The preferred composition of suchparticles is the same as that described for pharmacologically activeingredient-containing particles.

The ratio of opioid agonist to opioid antagonist in the pharmaceuticaldosage forms according to the invention is preferably 1:1 to 3:1 byweight, for example, about 2:1 by weight.

In another preferred embodiment, neither the particles nor thepharmaceutical dosage form comprise any opioid antagonist.

Preferably, the pharmaceutical dosage form according to the inventioncontains more than 20 wt.-%, more preferably more than 30 wt.-%, stillmore preferably more than 40 wt.-%, yet more preferably more than 50wt.-%, most preferably more than 60 wt.-%, and in particular more than70 wt.-% of compounds which are not or hardly soluble in ethanol withrespect to the total weight of the pharmaceutical dosage form.

For the purpose of specification, compounds which are not or hardlysoluble in ethanol have a maximum solubility in aqueous ethanol (96%) atroom temperature of preferably less than 1000 mg/L, more preferably lessthan 800 mg/L, even more preferably less than 500 mg/L, most preferablyless than 100 mg/L and in particular less than 10 mg/L or less than 1mg/L.

Preferably, the pharmaceutical dosage form according to the inventioncontains more than 50 wt.-%, more preferably more than 60 wt.-%, stillmore preferably more than 70 wt.-%, yet more preferably more than 80wt.-%, most preferably more than 90 wt.-%, and in particular more than95 wt.-% of polymers which are not or hardly soluble in ethanol withrespect to the overall amount of polymers contained in thepharmaceutical dosage form.

Preferred polymers which are not or hardly soluble in ethanol accordingto the invention are xanthan, guar gum and some types of HPMC. Theskilled person knows what types of HPMC are not or hardly soluble inethanol within the sense of the invention.

In a particularly preferred embodiment, the entire pharmaceutical dosageform according to the invention contains polymers which are not orhardly soluble in ethanol and polymers which are soluble in ethanol,wherein the amount of polymers which are not or hardly soluble inethanol relative to the total amount of polymers contained in the dosageform is 30 to 100 wt.-%, more preferably 50 to 100 wt.-%, still morepreferably 60 to 95 wt.-% or 100 wt.-%, yet more preferably 70 to 90wt.-% or 100 wt.-%, most preferably 80 to 90 wt.-% or 90 to 100 wt.-%,and in particular more than 95 wt.-% or more than 99 wt.-%.

Preferred compositions of the pharmaceutical dosage form or, when thepharmaceutical dosage form is multiparticulate, of the particles aresummarized as embodiments B¹ to B⁶ in the table here below:

wt.-% ^(a)) B¹ B² B³ B⁴ B⁵ B⁶ pharmacologically active ingredient 40 ±10 40 ± 5  35 ± 10 33 ± 10 33 ± 10 33 ± 10 EVA polymer 40 ± 10 40 ± 5 50 ± 15 57 ± 20 60 ± 20 67 ± 15 additional prolonged release matrix 10 ±10 10 ± 10 15 ± 10 10 ± 7  7.5 ± 5  10 ± 10 material excipients 10 ± 1010 ± 10 5 ± 5 5 ± 5 5 ± 5 5 ± 5 ^(a)) relative to the total weight ofthe dosage form and particles, respectively.

The subjects to which the pharmaceutical dosage forms according to theinvention can be administered are not particularly limited. Preferably,the subjects are animals, more preferably human beings.

The pharmaceutical dosage form according to the invention or, when it ismultiparticulate, the particles that contain the pharmacologicallyactive ingredient are preferably thermoformed, preferably bymelt-extrusion, although also other methods of thermoforming may beuseful, such as press-molding at elevated temperature or heating ofcompacts that were manufactured by conventional compression in a firststep and then heated above the softening temperature of the EVA polymerand the prolonged release matrix material, respectively, in a secondstep to form break resistant, hardened compacts, i.e. monolithic dosageforms or particles, respectively. In this regard, thermoformingpreferably means the forming or molding of a mass after, before orduring the application of heat. Preferably, thermoforming is performedby hot-melt extrusion.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is hot-melt extruded.

In a preferred embodiment, hot-melt extrusion is performed by means of atwin-screw-extruder. Melt extrusion preferably provides a melt-extrudedstrand that is preferably cut into monoliths, which are then optionallycompressed and formed. Preferably, compression is achieved by means of adie and a punch, preferably from a monolithic mass obtained by meltextrusion. If obtained via melt extrusion, the compressing step ispreferably carried out with a monolithic mass exhibiting ambienttemperature, that is, a temperature in the range from 20 to 25° C.

The strands obtained by way of extrusion can either be subjected to thecompression step as such or can be cut prior to the compression step.This cutting can be performed by usual techniques, for example usingrotating knives or compressed air, at elevated temperature, e.g. whenthe extruded stand is still warm due to hot-melt extrusion, or atambient temperature, i.e. after the extruded strand has been allowed tocool down. When the extruded strand is still warm, singulation of theextruded strand into extruded monolithic pharmaceutical dosage forms andparticles, respectively, is preferably performed by cutting the extrudedstrand immediately after it has exited the extrusion die.

However, when the extruded strand is cut in the cooled state, subsequentsingulation of the extruded strand is preferably performed by optionallytransporting the still hot extruded strand by means of conveyor belts,allowing it to cool down and to congeal, and subsequently cutting it.Alternatively, the shaping can take place as described in EP-A 240 906by the extrudate being passed between two counter-rotating calenderrolls and being shaped directly to pharmaceutical dosage forms andparticles, respectively. It is of course also possible to subject theextruded strands to the compression step or to the cutting step whenstill warm, that is more or less immediately after the extrusion step.The extrusion is preferably carried out by means of a twin-screwextruder.

The pharmaceutical dosage forms and particles, respectively, accordingto the invention may be produced by different processes, theparticularly preferred of which are explained in greater detail below.Several suitable processes have already been described in the prior art.In this regard it can be referred to, e.g., WO 2005/016313, WO2005/016314, WO 2005/063214, WO 2005/102286, WO 2006/002883, WO2006/002884, WO 2006/002886, WO 2006/082097, and WO 2006/082099.

In general, the process for the production of the particles according tothe invention preferably comprises the following steps:

-   (a) mixing all ingredients;-   (b) optionally pre-forming the mixture obtained from step (a),    preferably by applying heat and/or force to the mixture obtained    from step (a), the quantity of heat supplied preferably not being    sufficient to heat the EVA polymer and the prolonged release matrix    material, respectively, up to its softening point;-   (c) hardening the mixture by applying heat and force, it being    possible to supply the heat during and/or before the application of    force and the quantity of heat supplied being sufficient to heat the    EVA polymer and the prolonged release matrix material, respectively,    at least up to its softening point; and thereafter allowing the    material to cool and removing the force-   (d) optionally singulating the hardened mixture;-   (e) optionally shaping the particles; and-   (f) optionally providing a film coating.

Heat may be supplied directly, e.g. by contact or by means of hot gassuch as hot air, or with the assistance of ultrasound; or is indirectlysupplied by friction and/or shear. Force may be applied and/or theparticles may be shaped for example by direct pharmaceutical dosageforming or with the assistance of a suitable extruder, particularly bymeans of a screw extruder equipped with one or two screws(single-screw-extruder and twin-screw-extruder, respectively) or bymeans of a planetary gear extruder.

The final shape of the pharmaceutical dosage forms and particles,respectively, may either be provided during the hardening of the mixtureby applying heat and force (step (c)) or in a subsequent step (step(e)). In both cases, the mixture of all components is preferably in theplastified state, i.e. preferably, shaping is performed at a temperatureat least above the softening point of the EVA polymer and the prolongedrelease matrix material, respectively. However, extrusion at lowertemperatures, e.g. ambient temperature, is also possible and may bepreferred.

Shaping can be performed, e.g., by means of a pharmaceutical dosageforming press comprising die and punches of appropriate shape.

Another aspect of the invention relates to a process for the productionof a tamper-resistant, oral pharmaceutical dosage form comprising thesteps of

-   (i) mixing a pharmacologically active ingredient, an ethylene-vinyl    acetate (EVA) polymer and optionally further excipients; and-   (ii) thermoforming the mixture obtained in step (i), wherein said    mixture is simultaneously or before or after the application of heat    subjected to pressure.

In a preferred embodiment, the tamper-resistant, oral pharmaceuticaldosage form which is produced by said process is according to thetamper-resistant, oral pharmaceutical dosage forms described above.

A particularly preferred process for the manufacture of the particlesaccording to the invention involves hot-melt extrusion. In this process,the pharmaceutical dosage forms and particles, respectively, accordingto the invention are produced by thermoforming with the assistance of anextruder, preferably without there being any observable consequentdiscoloration of the extrudate.

This process is characterized in that

-   a) all components are mixed,-   b) the resultant mixture is heated in the extruder at least up to    the softening point of the EVA polymer and the prolonged release    matrix material, respectively, and extruded through the outlet    orifice of the extruder by application of force,-   c) the still plastic extrudate is singulated and formed into the    pharmaceutical dosage forms and particles, respectively, or-   d) the cooled and optionally reheated singulated extrudate is formed    into the pharmaceutical dosage forms and particles, respectively.

Mixing of the components according to process step a) may also proceedin the extruder.

The components may also be mixed in a mixer known to the person skilledin the art. The mixer may, for example, be a roll mixer, shaking mixer,shear mixer or compulsory mixer.

The, preferably molten, mixture which has been heated in the extruder atleast up to the softening point of the EVA polymer and the prolongedrelease matrix material, respectively, is extruded from the extruderthrough a die with at least one bore.

The process according to the invention requires the use of suitableextruders, preferably screw extruders. Screw extruders which areequipped with two screws (twin-screw-extruders) are particularlypreferred.

In a preferred embodiment, extrusion is performed in the absence ofwater, i.e., no water is added. However, traces of water (e.g., causedby atmospheric humidity) may be present.

The extruded strand is preferably water-free, which preferably meansthat the water content of the extruded strand is preferably at most 10wt.-%, or at most 7.5 wt.-%, or at most 5.0 wt.-%, or at most 4.0 wt.-%,or at most 3.0 wt.-%, or at most 2.0 wt.-%, more preferably at most 1.7wt.-%, still more preferably at most 1.5 wt.-%, yet more preferably atmost 1.3 wt.-%, even more preferably at most 1.0 wt.-%, most preferablyat most 0.7 wt.-%, and in particular at most 0.5 wt.-%.

The extruder preferably comprises at least two temperature zones, withheating of the mixture at least up to the softening point of the EVApolymer and the prolonged release matrix material, respectively,proceeding in the first zone, which is downstream from a feed zone andoptionally mixing zone. The throughput of the mixture is preferably from1.0 kg to 15 kg/hour. In a preferred embodiment, the throughput is from0.2 kg/hour to 3.5 kg/hour. In another preferred embodiment, thethroughput is from 4 to 15 kg/hour.

In a preferred embodiment, the die head pressure is within the range offrom 0.5 to 200 bar. The die head pressure can be adjusted inter alia bydie geometry, temperature profile, extrusion speed, number of bores inthe dies, screw configuration, first feeding steps in the extruder, andthe like.

In a preferred embodiment, the die head pressure is within the range offrom 20±19 bar, more preferably 20±15 bar, and in particular 20±10 bar;or the die head pressure is within the range of from 30±20 bar, morepreferably 30±15 bar, and in particular 30±10 bar; or the die headpressure is within the range of from 40±20 bar, more preferably 40±15bar, and in particular 40±10 bar; or the die head pressure is within therange of from 50±20 bar, more preferably 50±15 bar, and in particular50±10 bar; or the die head pressure is within the range of from 60±20bar, more preferably 60±15 bar, and in particular 60±10 bar; or the diehead pressure is within the range of from 70±20 bar, more preferably70±15 bar, and in particular 70±10 bar; or the die head pressure iswithin the range of from 80±20 bar, more preferably 80±15 bar, and inparticular 80±10 bar; or the die head pressure is within the range offrom 90±20 bar, more preferably 90±15 bar, and in particular 90±10 bar;or the die head pressure is within the range of from 100±20 bar, morepreferably 100±15 bar, and in particular 100±10 bar.

The die geometry or the geometry of the bores is freely selectable. Thedie or the bores may accordingly exhibit a flat (film), round, oblong oroval cross-section, wherein the round cross-section preferably has adiameter of 0.1 mm to 2 mm for extruded particles and a larger diameterfor extruded monolithic pharmaceutical dosage forms. Preferably, the dieor the bores have a round cross-section. The casing of the extruder usedaccording to the invention may be heated or cooled. The correspondingtemperature control, i.e. heating or cooling, is so arranged that themixture to be extruded exhibits at least an average temperature (producttemperature) corresponding to the softening temperature of the prolongedrelease matrix material and does not rise above a temperature at whichthe pharmacologically active ingredient to be processed may be damaged.Preferably, the temperature of the mixture to be extruded is adjusted tobelow 180° C., preferably below 150° C., but at least to the softeningtemperature of the EVA polymer and the prolonged release matrixmaterial, respectively. Typical extrusion temperatures are 120° C. and150° C.

In a preferred embodiment, the extruder torque is within the range offrom 30 to 95%. Extruder torque can be adjusted inter alia by diegeometry, temperature profile, extrusion speed, number of bores in thedies, screw configuration, first feeding steps in the extruder, and thelike.

After extrusion of the molten mixture and optional cooling of theextruded strand or extruded strands, the extrudates are preferablysingulated. This singulation may preferably be performed by cutting upthe extrudates by means of revolving or rotating knives, wires, bladesor with the assistance of laser cutters.

Preferably, intermediate or final storage of the optionally singulatedextrudate or the final shape of the pharmaceutical dosage forms andparticles, respectively, according to the invention is performed underoxygen-free atmosphere which may be achieved, e.g., by means ofoxygen-scavengers.

The singulated extrudate may be press-formed into pharmaceutical dosageforms and particles, respectively, in order to impart the final shape tothe pharmaceutical dosage forms and particles, respectively.

The application of force in the extruder onto the at least plasticizedmixture is adjusted by controlling the rotational speed of the conveyingdevice in the extruder and the geometry thereof and by dimensioning theoutlet orifice in such a manner that the pressure necessary forextruding the plasticized mixture is built up in the extruder,preferably immediately prior to extrusion. The extrusion parameterswhich, for each particular composition, are necessary to give rise to apharmaceutical dosage form with desired mechanical properties, may beestablished by simple preliminary testing.

For example but not limiting, extrusion may be performed by means of atwin-screw-extruder type ZSE 18 or ZSE 27 (Leistritz, Nurnberg, Germany)or Thermo Scientific* Pharma 16 HME, screw diameters of 16, 18 or 27 mm.Screws having eccentric or blunt ends may be used. A heatable die with around bore or with a multitude of bores each having a diameter of 0.2,0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2.0, 3.0, 4.0, 5.0 or 6.0 mm maybe used. The extrusion parameters may be adjusted e.g. to the followingvalues: rotational speed of the screws: 120 Upm; delivery rate 0.5 kg/hfor Pharma 16, 2 kg/h for a ZSE 18 or 8 kg/h for a ZSE 27; producttemperature: in front of die 100 to 125° C. and behind die 125 to 135°C.; and jacket temperature: 110° C.

Preferably, extrusion is performed by means of twin-screw-extruders orplanetary-gear-extruders, twin-screw extruders (co-rotating orcontra-rotating) being particularly preferred.

The pharmaceutical dosage forms and particles, respectively, accordingto the invention are preferably produced by thermoforming with theassistance of an extruder without any observable consequentdiscoloration of the extrudates.

The process for the preparation of the pharmaceutical dosage forms andparticles, respectively, according to the invention is preferablyperformed continuously. Preferably, the process involves the extrusionof a homogeneous mixture of all components. It is particularlyadvantageous if the thus obtained intermediate, e.g. the strand obtainedby extrusion, exhibits uniform properties. Particularly desirable areuniform density, uniform distribution of the active compound, uniformmechanical properties, uniform porosity, uniform appearance of thesurface, etc. Only under these circumstances the uniformity of thepharmacological properties, such as the stability of the releaseprofile, may be ensured and the amount of rejects can be kept low.

Preferably, the pharmaceutical dosage form is multiparticulate and theparticles according to the invention can be regarded as “extrudedpellets”. The term “extruded pellets” has structural implications whichare understood by persons skilled in the art. A person skilled in theart knows that pelletized pharmaceutical dosage forms can be prepared bya number of techniques, including:

-   -   drug layering on nonpareil sugar or microcrystalline cellulose        beads,    -   spray drying,    -   spray congealing,    -   rotogranulation,    -   hot-melt extrusion,    -   spheronization of low melting materials, or    -   extrusion-spheronization of a wet mass.

Accordingly, “extruded pellets” can be obtained either by hot-meltextrusion or by extrusion-spheronization.

“Extruded pellets” can be distinguished from other types of pelletsbecause they are structurally different. For example, drug layering onnonpareils yields multilayered pellets having a core, whereas extrusiontypically yields a monolithic mass comprising a homogeneous mixture ofall ingredients. Similarly, spray drying and spray congealing typicallyyield spheres, whereas extrusion typically yields cylindrical extrudateswhich can be subsequently spheronized.

The structural differences between “extruded pellets” and “agglomeratedpellets” are significant because they may affect the release of activesubstances from the pellets and consequently result in differentpharmacological profiles. Therefore, a person skilled in thepharmaceutical formulation art would not consider “extruded pellets” tobe equivalent to “agglomerated pellets”.

The pharmaceutical dosage forms according to the invention may beprepared by any conventional method. Preferably, however, thepharmaceutical dosage forms are prepared by compression. Thus, particlesas hereinbefore defined are preferably mixed, e.g. blended and/orgranulated (e.g. wet granulated), with outer matrix material and theresulting mix (e.g. blend or granulate) is then compressed, preferablyin molds, to form pharmaceutical dosage forms. It is also envisaged thatthe particles herein described may be incorporated into a matrix usingother processes, such as by melt granulation (e.g. using fatty alcoholsand/or water-soluble waxes and/or water-insoluble waxes) or high sheargranulation, followed by compression.

When the pharmaceutical dosage forms according to the invention aremanufactured by means of an eccentric press, the compression force ispreferably within the range of from 5 to 15 kN. When the pharmaceuticaldosage forms according to the invention are manufactured by means of arotating press, the compression force is preferably within the range offrom 5 to 40 kN, in certain embodiments >25 kN, in other embodimentsabout 13 kN.

Another aspect of the invention relates to a tamper-resistant, oralpharmaceutical dosage form which is obtainable by any of the processesdescribed above.

The pharmaceutical dosage form according to the invention ischaracterized by excellent storage stability. Preferably, after storagefor 4 weeks at 40° C. and 75% rel. humidity, the content ofpharmacologically active ingredient amounts to at least 98.0%, morepreferably at least 98.5%, still more preferably at least 99.0%, yetmore preferably at least 99.2%, most preferably at least 99.4% and inparticular at least 99.6%, of its original content before storage.Suitable methods for measuring the content of the pharmacologicallyactive ingredient in the pharmaceutical dosage form are known to theskilled artisan. In this regard it is referred to the Eur. Ph. or theUSP, especially to reversed phase HPLC analysis. Preferably, thepharmaceutical dosage form is stored in closed, preferably sealedcontainers.

The pharmaceutical dosage forms according to the invention may be usedin medicine, e.g. as an analgesic. The pharmaceutical dosage forms aretherefore particularly suitable for the treatment or management of pain.In such pharmaceutical dosage forms, the pharmacologically activeingredient preferably is analgesically effective.

A further aspect of the invention relates to the pharmaceutical dosageform as described above for use in the treatment of pain.

A further aspect of the invention relates to the use of thepharmacologically active ingredient for the manufacture of apharmaceutical dosage form as described above for treating pain.

A further aspect of the invention relates to a method of treating paincomprising the administration of the pharmaceutical dosage form asdescribed above to a subject in need thereof.

A further aspect according to the invention relates to the use of apharmaceutical dosage form as described above for providing prolongedrelease of the pharmacologically active ingredient contained therein.

A further aspect according to the invention relates to the use of apharmaceutical dosage form as described above for avoiding or hinderingthe abuse of the pharmacologically active ingredient contained therein.

A further aspect according to the invention relates to the use of apharmaceutical dosage form as described above for avoiding or hinderingthe unintentional overdose of the pharmacologically active ingredientcontained therein.

In this regard, the invention also relates to the use of apharmaceutical dosage form as described above for the prophylaxis and/orthe treatment of a disorder, thereby preventing an overdose of thepharmacologically active ingredient, particularly due to comminution ofthe pharmaceutical dosage form by mechanical action.

In a particularly preferred embodiment,

-   -   the pharmaceutical dosage form according to the invention is        monolithic or multiparticulate or a MUPS formulation; and/or    -   the pharmaceutical dosage form according to the invention is        hot-melt extruded; and/or    -   the pharmaceutical dosage form according to the invention        provides prolonged release of the pharmacologically active        ingredient having psychotropic action; and/or    -   the pharmacologically active ingredient having psychotropic        action is an opioid or a physiologically acceptable salt        thereof; and/or    -   the content of the pharmacologically active ingredient is within        the range of from 1 to 35 wt.-%, based on the total weight of        the pharmaceutical dosage form; and/or    -   the EVA polymer comprises repetition units derived from ethylene        and vinyl acetate and/or vinyl alcohol; and/or    -   the EVA polymer contains 60±30 wt.-%, more preferably 60±5 wt.-%        of ethylene repetition units, relative to the total weight of        the EVA polymer; and/or    -   the EVA polymer has a melt flow rate at 190° C. and 2.16 kg of        52±2 g/10 min measured according to ASTM D1238; and/or    -   the content of the EVA polymer is within the range of from 45 to        70 wt.-%, relative to the total weight of the pharmaceutical        dosage form or, when the pharmaceutical dosage form is        multiparticulate, relative to the total weight of the particles        that contain the pharmacologically active ingredient; and/or    -   the pharmacologically active ingredient is embedded in a        prolonged release matrix containing the EVA polymer as prolonged        release matrix material and additional prolonged release matrix        material; wherein        -   the content of the additional prolonged release matrix            material is in the range of 5 to 30 wt.-%, relative to the            total weight of the prolonged release matrix; and/or        -   the additional prolonged release matrix material is a            polyalkylene oxide, preferably a polyethylene oxide having a            weight average molecular weight of at least 5,000,000 g/mol;            or        -   the additional prolonged release matrix material is a            mixture of polyvinyl pyrrolidone and polyvinyl acetate,            wherein said mixture has a K-value in the range of from 60            to 65, measured in a 1% solution in tetrahydrofurane            according to the method described in the USP and Ph. Eur.            monographs “Povidone”, wherein the weight ratio between            polyvinyl acetate and polyvinyl pyrrolidone is in the range            of 4.5:1 to 3.5:1; or        -   the additional prolonged release matrix material is an            anionic acrylic polymer, preferably a polyacrylic acid            polymer which is crosslinked with ally pentaerythritol            having a viscosity of 4,000 to 11,000 mPa·s, measured with a            Brookfield RVT, 20 rpm, spindle no. 5 at 25° C. and 0.5            wt.-% neutralized to pH 7.3-7.8.

EXAMPLES

For manufacturing the pellets, mixtures of the pharmacologically activeingredient, EVA and excipients were produced by weighing the ingredients(batch size 500.0 g), sieving (Mesh size 1.0 mm), blending in a Bohle LM40 MC 20, followed by extrusion using a Leistritz ZSE 18 melt extrudertype MICRO 18 GL-40D Pharma (melt temperature 124° C., screw rotationspeed 100 rpm, die diameter 1.0 mm, melt pressure 1-4 bar). The extrudedstrands were cooled in ambient air and were manually cut yieldingpellets.

General procedure 1 (GP1) for manufacturing the cut rods: mixtures ofthe pharmacologically active ingredient, EVA and excipients wereproduced by weighing the ingredients (batch size 500.0 g), sieving (Meshsize 1.0 mm), blending in a Bohle LM 40 MC 20, followed by extrusionusing a Leistritz Micro 18 HME (melt temperature ca. 124° C., screwrotation speed 50-100 rpm, die diameter 5.0 mm, melt pressure 16-47bar). The extruded strands were cooled in ambient air and were manuallycut with a hot knife into cut rods.

General procedure 2 (GP2) for manufacturing the cut rods: mixtures ofthe pharmacologically active ingredient, EVA and excipients wereproduced by weighing the ingredients (batch size 500.0 g), sieving (Meshsize 1.0 mm), blending in a Bohle LM 40 MC 20, followed by extrusionusing a Leistritz Micro 27 lab extruder (melt temperature ca. 124° C.,screw rotation speed 50-100 rpm, die diameter 5.0 mm, melt pressure16-47 bar). The extruded strands were cooled in ambient air and weremanually cut with a hot knife into cut rods.

The pellets and cut rods, respectively, were subjected to differenttests in order to assess the tamper-resistance with respect to thepharmacologically active ingredient contained in the pellets and cutrods, respectively.

Materials

-   Elvax® 40W ethylene-vinyl acetate copolymer (40 wt.-% vinyl acetate    comonomer)-   Elvax® 40L-03 ethylene-vinyl acetate copolymer (40 wt.-% vinyl    acetate comonomer)-   Elvax® 220W ethylene-vinyl acetate copolymer (28 wt.-% vinyl acetate    comonomer)-   Elvax® 265 ethylene-vinyl acetate copolymer (28 wt.-% vinyl acetate    comonomer)-   Elvax® 660 ethylene-vinyl acetate copolymer (12 wt.-% vinyl acetate    comonomer)-   PEO 7 Mio. polyethylene oxide (7 mio)-   Kollidon SR mixture of polyvinyl acetate and polyvinyl pyrrolidone-   Carbopol 71 G polymer of acrylic acid crosslinked with allyl ethers    of pentaerythritol-   Xanthan a polysaccharide comprising pentasaccharide repeat units    comprising glucose, mannose and glucuronic acid-   HPMC hydroxypropylmethylcellulose-   Kollicoat IR polyvinyl alcohol-polyethylene glycol graft copolymer

Example 1

Pellets were prepared having the following composition:

substance per tablet [mg] amount [%] Tramadol HCl 122.33 34.95 Elvax ®40W 175.00 50.00 PEO 7 Mio. 52.67 15.05 total 350.00 100.00

Pellets were ground with a commercial coffee mill, type Bosch MKM6000,180W, Typ KM13 for 2 min. Afterwards, the ground pellets were subjectedto a sieving analysis. The result of which is summarized in FIG. 1.

The release profile of tramadol HCl from the pellets was determinedunder in vitro conditions using the basket method according to Ph. Eur.at 75 rpm in 900 mL of buffered SIF sp (pH 6.8) (without sinker, n=3).The results are summarized in FIG. 3.

Example 2

Pellets were prepared having the following composition:

substance per tablet [mg] amount [%] Tramadol HCl 116.48 33.28 Elvax ®40W 233.52 66.72 total 350.00 100.00

Pellets were ground with a commercial coffee mill, type Bosch MKM6000,180W, Typ KM13 for 2 min. Afterwards, the ground pellets were subjectedto a sieving analysis. The result of which is summarized in FIG. 2.

To simulate an addict's attempt at preparing an i.v. injection, pelletswere ground with a commercial coffee mill, type Bosch MKM6000, 180W, TypKM13 for 2 min followed by extraction in boiled water for 5 min. Theresults are summarized in the below table.

TABLE 1 simulated preparation of i.v. injection. intact ground content[%] 1 13.56 39.62 (n = 3) 2 13.34 29.49 3 12.48 25.98 mean [%] 13.1331.70

The release profiles of tramadol HCl from the pellets were determinedunder in vitro conditions using the basket method according to Ph. Eur.at 75 rpm in 900 mL of buffered SIF sp (pH 6.8) and in 900 mL of 40%ethanol in 0.1 N HCl, respectively, (without sinker, n=3). The resultsare summarized in FIGS. 3 and 4.

Example 3

Pellets were prepared having the following composition:

substance per tablet [mg] amount [%] Tramadol HCl 116.48 33.28 Elvax ®40W 198.52 56.72 Kollidon SR 35.00 10.00 total 350.00 100.00

To simulate an addict's attempt at preparing an i.v. injection, pelletswere ground with a commercial coffee mill, type Bosch MKM6000, 180W, TypKM13 for 2 min followed by extraction in boiled water for 5 min. Theresults are summarized in the below table.

TABLE 2 simulated preparation of i.v. injection. intact ground content[%] 1 16.41 23.98 (n = 3) 2 19.58 30.52 3 15.99 26.25 mean [%] 17.3326.92

The release profile of tramadol HCl from the pellets was determinedunder in vitro conditions using the basket method according to Ph. Eur.at 75 rpm in 900 mL of buffered SIF sp (pH 6.8) (without sinker, n=3).The results are summarized in FIG. 3.

Example 3A

Cut rods were prepared according to GP1 having the same composition asthe pellets of Example 3.

The release profile of tramadol HCl from the cut rods was determinedunder in vitro conditions using the paddle method according to Ph. Eur.at 50 rpm in 900 mL of buffered SIF sp (pH 6.8) (without sinker, n=3).The results are summarized in FIG. 5.

Example 4

Pellets were prepared having the following composition:

substance per tablet [mg] amount [%] Tramadol HCl 116.48 33.28 Elvax ®40W 207.27 59.22 Carbopol 71G 26.25 7.50 total 350.00 100.00

To simulate an addict's attempt at preparing an i.v. injection, pelletswere ground with a commercial coffee mill, type Bosch MKM6000, 180W, TypKM13 for 2 min followed by extraction in boiled water for 5 min. Theresults are summarized in the below table.

TABLE 3 simulated preparation of i.v. injection. intact ground content[%] 1 11.20 42.90 (n = 3) 2 21.31 44.86 3 32.67 33.42 mean [%] 21.7340.39

The release profiles of tramadol HCl from the pellets were determinedunder in vitro conditions using the basket method according to Ph. Eur.at 75 rpm in 900 mL of buffered SIF sp (pH 6.8) and in 900 mL of 40%ethanol in 0.1 N HCl, respectively, (without sinker, n=3). The resultsare summarized in FIGS. 3 and 4.

Example 4A

Cut rods were prepared according to GP1 having the same composition asthe pellets of Example 4.

To simulate an addict's attempt at preparing an i.v. injection, cut rodswere ground with a commercial coffee mill, type Bosch MKM6000, 180W, TypKM13 for 2 min followed by extraction in boiled water for 5 min. Theresults are summarized in the below table.

TABLE 4 simulated preparation of i.v. injection. intact ground content[%] 1 29.70 84.71 (n = 3) 2 30.99 79.44 3 38.45 53.18 mean [%] 33.0572.44

The cut rods displayed a breaking strength (resistance to crushing) of1000 N (average value, n=10) determined with a Zwick Z 2.5 materialstester, F_(max)=2.5 kN, maximum draw: 1150 mm.

The release profile of tramadol HCl from the cut rods was determinedunder in vitro conditions using the paddle method according to Ph. Eur.at 50 rpm in 900 mL of buffered SIF sp (pH 6.8) (without sinker, n=3).The results are summarized in FIG. 5.

Example 5

Pellets were prepared having the following composition:

substance per tablet [mg] amount [%] Tramadol HCl 116.48 33.28 Elvax ®220W 233.52 66.72 total 350.00 100.00

Example 5A

Cut rods were according to GP1 prepared having the same composition asthe pellets of Example 5.

The release profile of tramadol HCl from the cut rods was determinedunder in vitro conditions using the paddle method according to Ph. Eur.at 50 rpm in 900 mL of buffered SIF sp (pH 6.8) (without sinker, n=3).The results are summarized in FIG. 5.

Example 6

Pellets were prepared having the following composition:

substance per tablet [mg] amount [%] Tramadol HCl 116.48 33.28 Elvax ®265 233.52 66.72 total 350.00 100.00

To simulate an addict's attempt at preparing an i.v. injection, pelletswere ground with a commercial coffee mill, type Bosch MKM6000, 180W, TypKM13 for 2 min followed by extraction in boiled water for 5 min. Theresults are summarized in the below table.

TABLE 5 simulated preparation of i.v. injection. intact ground content[%] 1 3.06 7.45 (n = 3) 2 4.51 8.02 3 4.47 8.38 mean [%] 4.01 7.95

The release profile of tramadol HCl from the pellets was determinedunder in vitro conditions using the basket method according to Ph. Eur.at 75 rpm in 900 mL of buffered SIF sp (pH 6.8) (without sinker, n=3).The results are summarized in FIG. 3.

Example 6A

Cut rods were prepared according to GP1 having the same composition asthe pellets of Example 6.

To simulate an addict's attempt at preparing an i.v. injection, cut rodswere ground with a commercial coffee mill, type Bosch MKM6000, 180W, TypKM13 for 2 min followed by extraction in boiled water for 5 min. Theresults are summarized in the below table.

TABLE 6 simulated preparation of i.v. injection. intact ground content[%] 1 2.38 38.58 (n = 3) 2 2.51 17.47 3 1.51 38.99 mean [%] 2.13 31.68

The cut rods displayed a breaking strength (resistance to crushing) of1000 N (average value, n=10) determined with a Zwick Z 2.5 materialstester, F_(max)=2.5 kN, maximum draw: 1150 mm.

The release profile of tramadol HCl from the cut rods was determinedunder in vitro conditions using the paddle method according to Ph. Eur.at 50 rpm in 900 mL of buffered SIF sp (pH 6.8) (without sinker, n=3).The results are summarized in FIG. 5.

Example 7

Pellets were prepared having the following composition:

substance per tablet [mg] amount [%] Tramadol HCl 116.48 33.28 Elvax ®40L-03 233.52 66.72 total 350.00 100.00

The release profile of tramadol HCl from the pellets was determinedunder in vitro conditions using the basket method according to Ph. Eur.at 75 rpm in 900 mL of buffered SIF sp (pH 6.8) (without sinker, n=3).The results are summarized in FIG. 3.

Example 7A

Cut rods were prepared according to GP1 having the same composition asthe pellets of Example 7.

The release profile of tramadol HCl from the cut rods was determinedunder in vitro conditions using the paddle method according to Ph. Eur.at 50 rpm in 900 mL of buffered SIF sp (pH 6.8) (without sinker, n=3).The results are summarized in FIG. 5.

Example 8

Pellets were prepared having the following composition:

substance per tablet [mg] amount [%] Tramadol HCl 116.48 33.28 Elvax ®660 233.52 66.72 total 350.00 100.00

The release profile of tramadol HCl from the pellets was determinedunder in vitro conditions using the basket method according to Ph. Eur.at 75 rpm in 900 mL of buffered SIF sp (pH 6.8) (without sinker, n=3).The results are summarized in FIG. 3.

Example 8A

Cut rods were prepared according to GP1 having the same composition asthe pellets of Example 8.

The release profile of tramadol HCl from the cut rods was determinedunder in vitro conditions using the paddle method according to Ph. Eur.at 50 rpm in 900 mL of buffered SIF sp (pH 6.8) (without sinker, n=3).The results are summarized in FIG. 5.

In examples 7 and 7A, and in examples 8 and 8A, respectively, thepharmacologically active substance was in both cases tramadol HCl, thereleasing polymer was EVA. The composition of both the cut rods (diediameter 1.0 mm) and the pellets (die diameter 5.0 mm) was identical.Considering FIGS. 3 and 5, it becomes evident that the particle size hadno influence on the release behavior of EVA, as in both cases aprolonged-release (PR) of tramadol HCl could be observed.

Example 9

Cut rods were prepared according to GP2 having the followingcomposition:

Substance per tablet [mg] amount [%] Tramadol HCl 50.00 14.30 Elvax EVA40W 212.50 60.7 Xanthan 35.00 10.00 HPMC 17.50 5.00 Carbopol 35.00 10.00total 350.00 100.00

The release profile of tramadol HCl from cut rods was determined underin vitro conditions using the paddle method according to Ph. Eur. at 75rpm in 600 mL of buffered SIF sp (pH 6.8) with sinker type 1, n=3. Theresults are shown in FIG. 6.

The release profile of tramadol HCl from cut rods was also determined inaqueous ethanol using the paddle method according to Ph. Eur. At 75 rpmin 600 mL of 0.1 N HCl 40% EtOH with sinker type 1, n=3. The results areshown in FIG. 7.

To simulate an addict's attempt at preparing an i.v. injection, anextraction was carried out according to example 2. The results aresummarized in the below table.

TABLE 7 simulated preparation of i.v. injection. intact manipulatedcontent 1 3.50 — [%] 2 1.49 — (n = 3) 3 3.31 — mean [%] 2.77 —

Example 10

Cut rods were prepared according to GP2 having the followingcomposition:

Substance per tablet [mg] amount [%] Tramadol HCl 50.00 14.30 Elvax EVA40W 107.50 30.70 Elvax 265A 105.00 30.00 Xanthan 35.00 10.00 KollicoatSR 52.50 15.00 total 350.00 100.00

The release profile of tramadol HCl from the cut rods was determinedunder in vitro conditions using the paddle method according to Ph. Eur.at 75 rpm in 600 mL of buffered SIF sp (pH 6.8) with sinker type 1, n=3.The results are summarized in FIG. 6.

The release profile of tramadol HCl from cut rods was also determined inaqueous ethanol using the paddle method according to Ph. Eur. At 75 rpmin 600 mL of 0.1 N HCl 40% EtOH with sinker type 1, n=3. The results aresummarized in FIG. 7.

To simulate an addict's attempt at preparing an i.v. injection, anextraction was carried out according to example 2. The results aresummarized in the below table.

TABLE 8 simulated preparation of i.v. injection. intact manipulatedcontent 1 2.65 — [%] 2 1.24 — (n = 3) 3 1.86 — mean [%] 1.92 —

Example 11

Cut rods were prepared according to GP2 having the followingcomposition:

Substance per tablet [mg] amount [%] Tramadol HCl 50.00 14.30 Elvax 265A195.00 55.70 Xanthan 35.00 10.00 Kollicoat IR 70.00 20.00 total 350.00100.00

The release profile of tramadol HCl from cut rods was determined underin vitro conditions using the paddle method according to Ph. Eur. at 75rpm in 600 mL of buffered SIF sp (pH 6.8) with sinker type 1, n=3. Theresults are summarized in FIG. 6.

The release profile of tramadol HCl from cut rods was also determined inaqueous ethanol using the paddle method according to Ph. Eur. At 75 rpmin 600 mL of 0.1 N HCl 40% EtOH with sinker type 1, n=3. The results aresummarized in FIG. 7.

To simulate an addict's attempt at preparing an i.v. injection, anextraction was carried out according to example 2. The results aresummarized in the below table.

TABLE 9 simulated preparation of i.v. injection. intact manipulatedcontent 1 15.15 — [%] 2 13.90 — (n = 3) 3 12.59 — mean [%] 13.26 —

Example 12

Cut rods were prepared according to GP2 having the followingcomposition:

Substance per tablet [mg] amount [%] Tramadol HCl 50.00 14.30 Elvax 265A125.00 35.70 Elvax 40W 70.00 20.00 Kollicoat IR 70.00 20.00 Xanthan35.00 10.00 total 350.00 100.00

The release profile of tramadol HCl from cut rods was determined underin vitro conditions using the paddle method according to Ph. Eur. at 75rpm in 600 mL of buffered SIF sp (pH 6.8) with sinker type 1, n=3. Theresults are summarized in FIG. 6.

The release profile of tramadol HCl from cut rods was also determined inaqueous ethanol using the paddle method according to Ph. Eur. At 75 rpmin 600 mL of 0.1 N HCl 40% EtOH with sinker type 1, n=3. The results aresummarized in FIG. 7.

To simulate an addict's attempt at preparing an i.v. injection, anextraction was carried out according to example 2. The results aresummarized in the below table.

TABLE 10 simulated preparation of i.v. injection. intact manipulatedcontent 1 15.29 — [%] 2 15.90 — (n = 3) 3 8.59 — mean [%] 13.26 —

Examples 9-12 demonstrate the resistance of EVA-containing formulationsagainst dose-dumping in aqueous ethanol. Comparing FIGS. 6 and 7, itbecomes evident that the dissolution behavior of the correspondingmonolithic form (i.e. cut rods with a die diameter of 5 mm) in aqueousethanol is equal to the dissolution behavior under in vitro conditions.Thus, the controlled release portion of the formulation cannot bedefeated by the extraction with ethanol or by the concomitant intake ofethanol.

For all examples 9-12, a manipulation of the cud rods did not allow awinding up of the pharmaceutically active ingredient.

Comparative Example 13

Pellets were prepared having the following composition:

per tablet Substance [mg] amount [%] Tapentadol HCl 116.48 33.28Hypromellose 100000 mPas 44.0 12.57 PEG 6000 35.00 10.00 alphaTocopherol 0.04 0.01 PEO 7 Mio 154.48 44.14 total 350.00 100.00

The release profiles of tapentadol HCl from pellets was determined underin vitro conditions using the paddle method according to Ph. Eur. at 50rpm in 900 mL 0.1N HCl (without sinker, n=3). The results are summarizedin FIG. 8.

Comparative Example 13A

Cut rods were prepared according to GP1 having the same composition asthe pellets of Example 13.

The release profile of tapentadol HCl from cut rods was determined underin vitro conditions using the paddle method according to Ph. Eur. at 50rpm in 900 mL 0.1N HCl (without sinker, n=3). The results are shown inFIG. 8.

In examples 13 and 13A, the pharmacologically active substance was inboth cases tapentadol HCl, the polymer releasing the substance was PEO.The composition of both the cut rods and the pellets was identical.Considering FIG. 8, it becomes evident that for pellets (die diameter1.0 mm), an immediate-release (IR) of tapentadol HCl could be observed,whereas for cut rods (die diameter 6.0 mm), a prolonged-release (PR) isobserved. Thus, for PEO and in contrast to EVA, the particle size has apronounced influence on the dissolution behavior of thepharmacologically active substance. The smaller the particles, thefaster the release.

In the above examples 1-12, the pharmacologically active substance is inall cases tramadol HCl, whereas in examples 13 and 13A, the substance istapentadol HCl. However, both tapentadol HCl and tramadol HCl show acomparable dissolution behavior and are both water-soluble; thedependency of the dissolution behavior on the particle size is thereforecomparable.

The invention claimed is:
 1. A tamper-resistant, oral pharmaceuticaldosage form comprising a homogeneous mixture of: (A) a pharmacologicallyactive ingredient having psychotropic action and (B) a prolonged releasematrix comprising 55 to 80 wt.-% relative to a total weight of thedosage form of an ethylene-vinyl acetate (EVA) polymer, wherein the EVApolymer provides resistance against solvent extraction, resistanceagainst grinding, and resistance against dose-dumping in aqueousethanol.
 2. The pharmaceutical dosage form according to claim 1, whereinthe EVA polymer comprises repetition units derived from ethylene andvinyl acetate and/or vinyl alcohol.
 3. The pharmaceutical dosage formaccording to claim 1, wherein the EVA polymer contains at least 50 wt.-%of ethylene repetition units, relative to the total weight of the EVApolymer.
 4. The pharmaceutical dosage form according to claim 3, whereinthe EVA polymer contains from 50 to 95 wt.-% of ethylene repetitionunits, relative to the total weight of the EVA polymer.
 5. Thepharmaceutical dosage form according to claim 1, wherein the EVA polymerhas a melt flow rate at 190° C. and 2.16 kg within the range of from 1to 160 g/10 min measured according to ASTM D1238.
 6. The pharmaceuticaldosage form according to claim 1, which is monolithic and has a breakingstrength of at least 300 N.
 7. The pharmaceutical dosage form accordingto claim 1, which is monolithic and has an extension in any direction ofat least 2.0 mm.
 8. The pharmaceutical dosage form according to claim 1,wherein the pharmacologically active ingredient is an opioid or aphysiologically acceptable salt thereof.
 9. The pharmaceutical dosageform according to claim 1, which is hot-melt extruded.
 10. A process forthe production of the tamper-resistant, oral pharmaceutical dosage formaccording to claim 1, said process comprising the steps of: (i) mixing apharmacologically active ingredient, 55 to 80 wt.-% relative to a totalweight of the dosage form of an ethylene-vinyl acetate (EVA) polymer,and optionally further excipients to form a mixture; and (ii)thermoforming the mixture obtained in step (i), wherein said mixture issimultaneously or before or after the application of heat subjected topressure.
 11. A tamper-resistant, oral pharmaceutical dosage formobtained by the process according to claim
 10. 12. A method of treatingpain in a patient, said method comprising administering to said patienta dosage form according to claim 1 wherein the pharmacologically activeingredient is an opioid or a physiologically acceptable salt thereof.13. The pharmaceutical dosage form according to claim 1, which ismultiparticulate, wherein at least a fraction of individual particleshave a breaking strength of at least 300 N.
 14. The pharmaceuticaldosage form according to claim 1, which is multiparticulate, whereinindividual drug-containing particles have an extension in any directionof at least 2.0 mm.